WO2004113277A2 - Methods and compositions for treating amyloid-related diseases - Google Patents
Methods and compositions for treating amyloid-related diseases Download PDFInfo
- Publication number
- WO2004113277A2 WO2004113277A2 PCT/IB2004/002337 IB2004002337W WO2004113277A2 WO 2004113277 A2 WO2004113277 A2 WO 2004113277A2 IB 2004002337 W IB2004002337 W IB 2004002337W WO 2004113277 A2 WO2004113277 A2 WO 2004113277A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amyloid
- compound
- subject
- pharmaceutical composition
- foregoing
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 249
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 129
- 201000010099 disease Diseases 0.000 title claims abstract description 107
- 239000000203 mixture Substances 0.000 title description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 337
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 91
- -1 benzoimidazolyl Chemical group 0.000 claims description 184
- 150000003839 salts Chemical class 0.000 claims description 122
- 208000024827 Alzheimer disease Diseases 0.000 claims description 118
- 230000003941 amyloidogenesis Effects 0.000 claims description 113
- 239000001257 hydrogen Substances 0.000 claims description 104
- 229910052739 hydrogen Inorganic materials 0.000 claims description 104
- 125000000217 alkyl group Chemical group 0.000 claims description 101
- 206010002022 amyloidosis Diseases 0.000 claims description 98
- 210000004556 brain Anatomy 0.000 claims description 89
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 150000002148 esters Chemical class 0.000 claims description 82
- 102000009091 Amyloidogenic Proteins Human genes 0.000 claims description 76
- 108010048112 Amyloidogenic Proteins Proteins 0.000 claims description 76
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 76
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 71
- 238000000151 deposition Methods 0.000 claims description 62
- 210000004027 cell Anatomy 0.000 claims description 56
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 54
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 49
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 49
- 230000008021 deposition Effects 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 125000003342 alkenyl group Chemical group 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 46
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 44
- 125000000304 alkynyl group Chemical group 0.000 claims description 44
- 238000011282 treatment Methods 0.000 claims description 43
- 235000001014 amino acid Nutrition 0.000 claims description 42
- 229940024606 amino acid Drugs 0.000 claims description 42
- 150000001413 amino acids Chemical class 0.000 claims description 41
- 230000007423 decrease Effects 0.000 claims description 41
- 229910052760 oxygen Inorganic materials 0.000 claims description 41
- 230000001225 therapeutic effect Effects 0.000 claims description 41
- 208000037259 Amyloid Plaque Diseases 0.000 claims description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 40
- 239000001301 oxygen Substances 0.000 claims description 40
- 125000002883 imidazolyl group Chemical group 0.000 claims description 38
- 239000000651 prodrug Substances 0.000 claims description 38
- 229940002612 prodrug Drugs 0.000 claims description 38
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 36
- 230000002401 inhibitory effect Effects 0.000 claims description 35
- 125000001425 triazolyl group Chemical group 0.000 claims description 35
- 238000012360 testing method Methods 0.000 claims description 32
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 30
- 125000000335 thiazolyl group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 29
- 206010012289 Dementia Diseases 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 208000010877 cognitive disease Diseases 0.000 claims description 26
- 230000001965 increasing effect Effects 0.000 claims description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 239000000470 constituent Substances 0.000 claims description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims description 23
- 150000001768 cations Chemical class 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 22
- 208000002780 macular degeneration Diseases 0.000 claims description 21
- 201000010374 Down Syndrome Diseases 0.000 claims description 20
- 206010044688 Trisomy 21 Diseases 0.000 claims description 20
- 230000003942 amyloidogenic effect Effects 0.000 claims description 20
- 230000006933 amyloid-beta aggregation Effects 0.000 claims description 19
- 230000003993 interaction Effects 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 18
- 230000007541 cellular toxicity Effects 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 claims description 17
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 claims description 17
- 238000009825 accumulation Methods 0.000 claims description 17
- 210000002469 basement membrane Anatomy 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000002091 cationic group Chemical group 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 17
- 208000023769 AA amyloidosis Diseases 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 16
- 210000000056 organ Anatomy 0.000 claims description 16
- 208000005531 Immunoglobulin Light-chain Amyloidosis Diseases 0.000 claims description 15
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 15
- 229940125396 insulin Drugs 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 208000023761 AL amyloidosis Diseases 0.000 claims description 14
- 102000004877 Insulin Human genes 0.000 claims description 14
- 108090001061 Insulin Proteins 0.000 claims description 14
- 230000035508 accumulation Effects 0.000 claims description 14
- 125000002619 bicyclic group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 230000001149 cognitive effect Effects 0.000 claims description 13
- 230000002265 prevention Effects 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 239000011593 sulfur Chemical group 0.000 claims description 13
- 206010061218 Inflammation Diseases 0.000 claims description 12
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
- 230000002490 cerebral effect Effects 0.000 claims description 12
- 230000004054 inflammatory process Effects 0.000 claims description 12
- 125000006413 ring segment Chemical group 0.000 claims description 12
- PLOPBXQQPZYQFA-AXPWDRQUSA-N amlintide Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CSSC1)[C@@H](C)O)C(C)C)C1=CC=CC=C1 PLOPBXQQPZYQFA-AXPWDRQUSA-N 0.000 claims description 11
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 238000000502 dialysis Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 230000004770 neurodegeneration Effects 0.000 claims description 11
- 208000034846 Familial Amyloid Neuropathies Diseases 0.000 claims description 10
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 10
- 206010019889 Hereditary neuropathic amyloidosis Diseases 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 230000006870 function Effects 0.000 claims description 10
- 201000008319 inclusion body myositis Diseases 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 201000007905 transthyretin amyloidosis Diseases 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 9
- 208000024777 Prion disease Diseases 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 231100000419 toxicity Toxicity 0.000 claims description 9
- 206010039966 Senile dementia Diseases 0.000 claims description 8
- 108010031545 amyloid K Proteins 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 230000003920 cognitive function Effects 0.000 claims description 8
- 238000001631 haemodialysis Methods 0.000 claims description 8
- 230000000322 hemodialysis Effects 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 201000004810 Vascular dementia Diseases 0.000 claims description 7
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- 210000001124 body fluid Anatomy 0.000 claims description 7
- 239000010839 body fluid Substances 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- 208000028698 Cognitive impairment Diseases 0.000 claims description 6
- 206010016202 Familial Amyloidosis Diseases 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 206010029350 Neurotoxicity Diseases 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 206010044221 Toxic encephalopathy Diseases 0.000 claims description 6
- 230000001746 atrial effect Effects 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 230000007135 neurotoxicity Effects 0.000 claims description 6
- 231100000228 neurotoxicity Toxicity 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical group FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 5
- 208000019736 Cranial nerve disease Diseases 0.000 claims description 5
- 206010061818 Disease progression Diseases 0.000 claims description 5
- 102000003886 Glycoproteins Human genes 0.000 claims description 5
- 108090000288 Glycoproteins Proteins 0.000 claims description 5
- 208000010190 Monoclonal Gammopathy of Undetermined Significance Diseases 0.000 claims description 5
- 108010050254 Presenilins Proteins 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 101150031224 app gene Proteins 0.000 claims description 5
- 229910052788 barium Inorganic materials 0.000 claims description 5
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 5
- 208000014826 cranial nerve neuropathy Diseases 0.000 claims description 5
- 230000005750 disease progression Effects 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 229910052742 iron Inorganic materials 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- 201000005328 monoclonal gammopathy of uncertain significance Diseases 0.000 claims description 5
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 5
- 230000002981 neuropathic effect Effects 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 208000027121 wild type ATTR amyloidosis Diseases 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 4
- 206010011878 Deafness Diseases 0.000 claims description 4
- 208000007054 Medullary Carcinoma Diseases 0.000 claims description 4
- 201000002795 Muckle-Wells syndrome Diseases 0.000 claims description 4
- 208000024780 Urticaria Diseases 0.000 claims description 4
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 4
- 230000005779 cell damage Effects 0.000 claims description 4
- 208000037887 cell injury Diseases 0.000 claims description 4
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 claims description 4
- 231100000895 deafness Toxicity 0.000 claims description 4
- 208000016354 hearing loss disease Diseases 0.000 claims description 4
- 201000001421 hyperglycemia Diseases 0.000 claims description 4
- 208000019715 inherited Creutzfeldt-Jakob disease Diseases 0.000 claims description 4
- 230000006724 microglial activation Effects 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 210000001685 thyroid gland Anatomy 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 3
- 230000008826 genomic mutation Effects 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 108700028369 Alleles Proteins 0.000 claims description 2
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002335 preservative effect Effects 0.000 claims description 2
- 230000006641 stabilisation Effects 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 24
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 4
- 206010037660 Pyrexia Diseases 0.000 claims 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 2
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 claims 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims 1
- 239000008240 homogeneous mixture Substances 0.000 claims 1
- 238000002657 hormone replacement therapy Methods 0.000 claims 1
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 229910001867 inorganic solvent Inorganic materials 0.000 claims 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 230000004850 protein–protein interaction Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 description 72
- 230000008499 blood brain barrier function Effects 0.000 description 42
- 210000001218 blood-brain barrier Anatomy 0.000 description 42
- 108090000623 proteins and genes Proteins 0.000 description 33
- 230000035772 mutation Effects 0.000 description 31
- 235000018102 proteins Nutrition 0.000 description 28
- 102000004169 proteins and genes Human genes 0.000 description 28
- 230000032258 transport Effects 0.000 description 26
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 229940079593 drug Drugs 0.000 description 23
- 208000035475 disorder Diseases 0.000 description 22
- 229940124597 therapeutic agent Drugs 0.000 description 21
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 19
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 18
- 239000013543 active substance Substances 0.000 description 17
- 210000002381 plasma Anatomy 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 238000012384 transportation and delivery Methods 0.000 description 15
- 239000013598 vector Substances 0.000 description 15
- 238000005755 formation reaction Methods 0.000 description 14
- 102000004196 processed proteins & peptides Human genes 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 13
- 230000019771 cognition Effects 0.000 description 13
- 239000012634 fragment Substances 0.000 description 13
- 230000001404 mediated effect Effects 0.000 description 13
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000015556 catabolic process Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 230000006378 damage Effects 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 239000000562 conjugate Substances 0.000 description 10
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 230000007170 pathology Effects 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000008685 targeting Effects 0.000 description 10
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 210000005013 brain tissue Anatomy 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 102000001049 Amyloid Human genes 0.000 description 8
- 108010094108 Amyloid Proteins 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- 108010067787 Proteoglycans Proteins 0.000 description 8
- 102000016611 Proteoglycans Human genes 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 238000010171 animal model Methods 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 239000012039 electrophile Substances 0.000 description 8
- 230000002708 enhancing effect Effects 0.000 description 8
- 210000000981 epithelium Anatomy 0.000 description 8
- 239000002502 liposome Substances 0.000 description 8
- 239000012038 nucleophile Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000012545 processing Methods 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 206010002023 Amyloidoses Diseases 0.000 description 7
- 108091016585 CD44 antigen Proteins 0.000 description 7
- 102000008055 Heparan Sulfate Proteoglycans Human genes 0.000 description 7
- 229920002971 Heparan sulfate Polymers 0.000 description 7
- 108010071690 Prealbumin Proteins 0.000 description 7
- 102000029797 Prion Human genes 0.000 description 7
- 108091000054 Prion Proteins 0.000 description 7
- 108090000054 Syndecan-2 Proteins 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 230000030833 cell death Effects 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000001087 myotubule Anatomy 0.000 description 7
- 210000002569 neuron Anatomy 0.000 description 7
- 230000002207 retinal effect Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 6
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- 102100022033 Presenilin-1 Human genes 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004442 acylamino group Chemical group 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 6
- 125000002877 alkyl aryl group Chemical group 0.000 description 6
- 125000000129 anionic group Chemical group 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 230000035515 penetration Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 108020004705 Codon Proteins 0.000 description 5
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 5
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 5
- 208000007487 Familial Cerebral Amyloid Angiopathy Diseases 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- 208000022435 Light chain deposition disease Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 206010036673 Primary amyloidosis Diseases 0.000 description 5
- 102000009190 Transthyretin Human genes 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 229940109239 creatinine Drugs 0.000 description 5
- 230000006735 deficit Effects 0.000 description 5
- 230000006866 deterioration Effects 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 125000004663 dialkyl amino group Chemical group 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 230000031998 transcytosis Effects 0.000 description 5
- 208000020687 AH amyloidosis Diseases 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 4
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 4
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 4
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 4
- 102400001282 Atrial natriuretic peptide Human genes 0.000 description 4
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 4
- 230000007082 Aβ accumulation Effects 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 208000032849 Hereditary cerebral hemorrhage with amyloidosis Diseases 0.000 description 4
- 238000008214 LDL Cholesterol Methods 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 102100022036 Presenilin-2 Human genes 0.000 description 4
- 229910006069 SO3H Inorganic materials 0.000 description 4
- 206010039811 Secondary amyloidosis Diseases 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000032683 aging Effects 0.000 description 4
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 4
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 125000001769 aryl amino group Chemical group 0.000 description 4
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 210000004958 brain cell Anatomy 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- 230000006999 cognitive decline Effects 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 125000004986 diarylamino group Chemical group 0.000 description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 208000015756 familial Alzheimer disease Diseases 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 210000004153 islets of langerhan Anatomy 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000000926 neurological effect Effects 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 208000033808 peripheral neuropathy Diseases 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 3
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 3
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 108010060159 Apolipoprotein E4 Proteins 0.000 description 3
- 108010071619 Apolipoproteins Proteins 0.000 description 3
- 102000007592 Apolipoproteins Human genes 0.000 description 3
- 108010025628 Apolipoproteins E Proteins 0.000 description 3
- 102000013918 Apolipoproteins E Human genes 0.000 description 3
- 206010003694 Atrophy Diseases 0.000 description 3
- 108090001008 Avidin Proteins 0.000 description 3
- 201000004569 Blindness Diseases 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920000045 Dermatan sulfate Polymers 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000015779 HDL Lipoproteins Human genes 0.000 description 3
- 108010010234 HDL Lipoproteins Proteins 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 206010023230 Joint stiffness Diseases 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- 229930064664 L-arginine Natural products 0.000 description 3
- 235000014852 L-arginine Nutrition 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical class CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010029164 Nephrotic syndrome Diseases 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 108010036933 Presenilin-1 Proteins 0.000 description 3
- 108010036908 Presenilin-2 Proteins 0.000 description 3
- 102000015499 Presenilins Human genes 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 206010062237 Renal impairment Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 108010033576 Transferrin Receptors Proteins 0.000 description 3
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 3
- 102100029290 Transthyretin Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 210000001642 activated microglia Anatomy 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 150000004703 alkoxides Chemical group 0.000 description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 210000002565 arteriole Anatomy 0.000 description 3
- 230000037444 atrophy Effects 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000008436 biogenesis Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 208000019902 chronic diarrheal disease Diseases 0.000 description 3
- 208000037976 chronic inflammation Diseases 0.000 description 3
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000001054 cortical effect Effects 0.000 description 3
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 description 3
- 229940051593 dermatan sulfate Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 201000006061 fatal familial insomnia Diseases 0.000 description 3
- 230000003619 fibrillary effect Effects 0.000 description 3
- 230000035557 fibrillogenesis Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 208000019855 heavy chain deposition disease Diseases 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 230000007388 microgliosis Effects 0.000 description 3
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 3
- 230000004768 organ dysfunction Effects 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 231100000857 poor renal function Toxicity 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 208000022256 primary systemic amyloidosis Diseases 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000012846 protein folding Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 230000004393 visual impairment Effects 0.000 description 3
- UQWNNUPJBDWRHC-UWVGGRQHSA-N (3s,4s)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid Chemical compound OC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1 UQWNNUPJBDWRHC-UWVGGRQHSA-N 0.000 description 2
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- PBLZLIFKVPJDCO-UHFFFAOYSA-N 12-aminododecanoic acid Chemical compound NCCCCCCCCCCCC(O)=O PBLZLIFKVPJDCO-UHFFFAOYSA-N 0.000 description 2
- TXHAHOVNFDVCCC-UHFFFAOYSA-N 2-(tert-butylazaniumyl)acetate Chemical compound CC(C)(C)NCC(O)=O TXHAHOVNFDVCCC-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CDULPPOISZOUTK-UHFFFAOYSA-N 2-azaniumyl-3,4-dihydro-1h-naphthalene-2-carboxylate Chemical compound C1=CC=C2CC(N)(C(O)=O)CCC2=C1 CDULPPOISZOUTK-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- UQTZMGFTRHFAAM-ZETCQYMHSA-N 3-iodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(I)=C1 UQTZMGFTRHFAAM-ZETCQYMHSA-N 0.000 description 2
- FBTSQILOGYXGMD-LURJTMIESA-N 3-nitro-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C([N+]([O-])=O)=C1 FBTSQILOGYXGMD-LURJTMIESA-N 0.000 description 2
- DFVFTMTWCUHJBL-UHFFFAOYSA-N 4-azaniumyl-3-hydroxy-6-methylheptanoate Chemical compound CC(C)CC(N)C(O)CC(O)=O DFVFTMTWCUHJBL-UHFFFAOYSA-N 0.000 description 2
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000024667 ABeta amyloidosis, Dutch type Diseases 0.000 description 2
- 208000023697 ABri amyloidosis Diseases 0.000 description 2
- 208000018282 ACys amyloidosis Diseases 0.000 description 2
- 208000017227 ADan amyloidosis Diseases 0.000 description 2
- 102100040026 Agrin Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102400000345 Angiotensin-2 Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 102400000667 Brain natriuretic peptide 32 Human genes 0.000 description 2
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 2
- 101800002247 Brain natriuretic peptide 45 Proteins 0.000 description 2
- 201000000166 CST3-related cerebral amyloid angiopathy Diseases 0.000 description 2
- 101710132601 Capsid protein Proteins 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 206010051290 Central nervous system lesion Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000012192 Cystatin C Human genes 0.000 description 2
- 108010061642 Cystatin C Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 102000004878 Gelsolin Human genes 0.000 description 2
- 108090001064 Gelsolin Proteins 0.000 description 2
- 208000003736 Gerstmann-Straussler-Scheinker Disease Diseases 0.000 description 2
- 206010072075 Gerstmann-Straussler-Scheinker syndrome Diseases 0.000 description 2
- 206010018341 Gliosis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000772194 Homo sapiens Transthyretin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 201000000162 ITM2B-related cerebral amyloid angiopathy 1 Diseases 0.000 description 2
- 201000000194 ITM2B-related cerebral amyloid angiopathy 2 Diseases 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 206010023232 Joint swelling Diseases 0.000 description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102100025818 Major prion protein Human genes 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102000016943 Muramidase Human genes 0.000 description 2
- 108010014251 Muramidase Proteins 0.000 description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 208000002774 Paraproteinemias Diseases 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- 230000023445 activated T cell autonomous cell death Effects 0.000 description 2
- 238000001994 activation Methods 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- 208000037875 astrocytosis Diseases 0.000 description 2
- 230000007341 astrogliosis Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 235000019504 cigarettes Nutrition 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 208000036536 dutch type ABeta amyloidosis Diseases 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 210000001723 extracellular space Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 150000002313 glycerolipids Chemical class 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 2
- 229940099584 lactobionate Drugs 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 229940070765 laurate Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 210000000274 microglia Anatomy 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 2
- 210000002241 neurite Anatomy 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 2
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 2
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 2
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 2
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 2
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 208000010626 plasma cell neoplasm Diseases 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 230000006337 proteolytic cleavage Effects 0.000 description 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000002755 pyrazolinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 229910052705 radium Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 208000008864 scrapie Diseases 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 125000004001 thioalkyl group Chemical group 0.000 description 2
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 229940036555 thyroid hormone Drugs 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 125000005490 tosylate group Chemical group 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 230000009278 visceral effect Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- JENWDDCMEATQSR-ONSKYXJOSA-N (2r)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-2-[[(2s)-2-[[2-[[2-[[(2s)-3-(4-hydroxyphenyl)-2-(methylamino)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]-met Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N(C)[C@@H](CCCN=C(N)N)C(=O)N[C@H](CC(C)C)C(=O)NCC)NC(=O)CNC(=O)CNC(=O)[C@H](CC=1C=CC(O)=CC=1)NC)C1=CC=CC=C1 JENWDDCMEATQSR-ONSKYXJOSA-N 0.000 description 1
- FQRURPFZTFUXEZ-MRVPVSSYSA-N (2s)-2,3,3,3-tetrafluoro-2-(n-fluoroanilino)propanoic acid Chemical compound OC(=O)[C@](F)(C(F)(F)F)N(F)C1=CC=CC=C1 FQRURPFZTFUXEZ-MRVPVSSYSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- RWLSBXBFZHDHHX-VIFPVBQESA-N (2s)-2-(naphthalen-2-ylamino)propanoic acid Chemical compound C1=CC=CC2=CC(N[C@@H](C)C(O)=O)=CC=C21 RWLSBXBFZHDHHX-VIFPVBQESA-N 0.000 description 1
- NRCSJHVDTAAISV-QMMMGPOBSA-N (2s)-2-amino-3-(3,4-dichlorophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(Cl)C(Cl)=C1 NRCSJHVDTAAISV-QMMMGPOBSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- CLFHFIGNDKHDPG-MPJXNKHJSA-N (4s)-5-[[(2s)-1-[[(2s)-1-[[(2r)-6-amino-1-[[(2s)-1-(8-aminooctylamino)-1-oxo-3-phenylpropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-4-[[(2s)-2-amino-4-methylsulfonylbutanoyl]amino]-5 Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCS(=O)(=O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCCCCCCCCN)C1=CN=CN1 CLFHFIGNDKHDPG-MPJXNKHJSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- 125000006313 (C5-C8) alkyl group Chemical group 0.000 description 1
- NQRKYASMKDDGHT-UHFFFAOYSA-N (aminooxy)acetic acid Chemical compound NOCC(O)=O NQRKYASMKDDGHT-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NYPYHUZRZVSYKL-UHFFFAOYSA-N -3,5-Diiodotyrosine Natural products OC(=O)C(N)CC1=CC(I)=C(O)C(I)=C1 NYPYHUZRZVSYKL-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BWKMGYQJPOAASG-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PAJPWUMXBYXFCZ-UHFFFAOYSA-N 1-aminocyclopropanecarboxylic acid Chemical compound OC(=O)C1(N)CC1 PAJPWUMXBYXFCZ-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GUOSQNAUYHMCRU-UHFFFAOYSA-N 11-Aminoundecanoic acid Chemical compound NCCCCCCCCCCC(O)=O GUOSQNAUYHMCRU-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- UVAMFBJPMUMURT-UHFFFAOYSA-N 2,3,4,5,6-pentafluorobenzenethiol Chemical class FC1=C(F)C(F)=C(S)C(F)=C1F UVAMFBJPMUMURT-UHFFFAOYSA-N 0.000 description 1
- LYLKYOCIGPXQFH-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-6-hydroxybenzenesulfonic acid Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1S(O)(=O)=O LYLKYOCIGPXQFH-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- VHPXSBIFWDAFMB-UHFFFAOYSA-N 2-amino-Delta(2)-thiazoline-4-carboxylic acid Chemical compound NC1=[NH+]C(C([O-])=O)CS1 VHPXSBIFWDAFMB-UHFFFAOYSA-N 0.000 description 1
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 description 1
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NYPYHUZRZVSYKL-ZETCQYMHSA-N 3,5-diiodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC(I)=C(O)C(I)=C1 NYPYHUZRZVSYKL-ZETCQYMHSA-N 0.000 description 1
- AJHPGXZOIAYYDW-UHFFFAOYSA-N 3-(2-cyanophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC1=CC=CC=C1C#N AJHPGXZOIAYYDW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MQHLULPKDLJASZ-QMMMGPOBSA-N 3-methyl-L-tyrosine zwitterion Chemical compound CC1=CC(C[C@H](N)C(O)=O)=CC=C1O MQHLULPKDLJASZ-QMMMGPOBSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-M 4-aminobenzoate Chemical compound NC1=CC=C(C([O-])=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-M 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- NIGWMJHCCYYCSF-QMMMGPOBSA-N 4-chloro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-QMMMGPOBSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical compound NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 description 1
- 101150079978 AGRN gene Proteins 0.000 description 1
- 101150037123 APOE gene Proteins 0.000 description 1
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 108700019743 Agrin Proteins 0.000 description 1
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 102000018430 Amyloid-beta precursor proteins Human genes 0.000 description 1
- 108050007552 Amyloid-beta precursor proteins Proteins 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102100029470 Apolipoprotein E Human genes 0.000 description 1
- 101710095339 Apolipoprotein E Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010061666 Autonomic neuropathy Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 102100021257 Beta-secretase 1 Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 208000024806 Brain atrophy Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 208000005024 Castleman disease Diseases 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000012988 Dithioester Substances 0.000 description 1
- 108010068583 E 2078 Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 101710163305 Fibril protein Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000003923 Hereditary Corneal Dystrophies Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000959594 Homo sapiens Agrin Proteins 0.000 description 1
- 101000823051 Homo sapiens Amyloid-beta precursor protein Proteins 0.000 description 1
- 101001000001 Homo sapiens Basement membrane-specific heparan sulfate proteoglycan core protein Proteins 0.000 description 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 229920000288 Keratan sulfate Polymers 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- LOOZZTFGSTZNRX-VIFPVBQESA-N L-Homotyrosine Chemical compound OC(=O)[C@@H](N)CCC1=CC=C(O)C=C1 LOOZZTFGSTZNRX-VIFPVBQESA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 description 1
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010025391 Macroglossia Diseases 0.000 description 1
- 244000137850 Marrubium vulgare Species 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 229910003827 NRaRb Inorganic materials 0.000 description 1
- NPKISZUVEBESJI-UHFFFAOYSA-N Nalpha-benzoyl-L-phenylalanine Natural products C=1C=CC=CC=1C(=O)NC(C(=O)O)CC1=CC=CC=C1 NPKISZUVEBESJI-UHFFFAOYSA-N 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910004727 OSO3H Inorganic materials 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010057178 Osteoarthropathies Diseases 0.000 description 1
- 206010031256 Osteomyelitis chronic Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- GKZIWHRNKRBEOH-HOTGVXAUSA-N Phe-Phe Chemical compound C([C@H]([NH3+])C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)C1=CC=CC=C1 GKZIWHRNKRBEOH-HOTGVXAUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100021923 Prolow-density lipoprotein receptor-related protein 1 Human genes 0.000 description 1
- 101710202113 Prolow-density lipoprotein receptor-related protein 1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037601 Pyelonephritis chronic Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 201000010848 Schnitzler Syndrome Diseases 0.000 description 1
- 102000054727 Serum Amyloid A Human genes 0.000 description 1
- 101710190759 Serum amyloid A protein Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 208000027207 Whipple disease Diseases 0.000 description 1
- 208000016463 Wild type ABeta2M amyloidosis Diseases 0.000 description 1
- BBAWTPDTGRXPDG-UHFFFAOYSA-N [1,3]thiazolo[4,5-b]pyridine Chemical compound C1=CC=C2SC=NC2=N1 BBAWTPDTGRXPDG-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000000476 acetylides Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000007000 age related cognitive decline Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000005157 alkyl carboxy group Chemical group 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000007450 amyloidogenic pathway Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N aniline-p-carboxylic acid Natural products NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000005512 benztetrazolyl group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004193 beta-amyloid degradation Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 230000007177 brain activity Effects 0.000 description 1
- 208000025698 brain inflammatory disease Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003576 central nervous system agent Substances 0.000 description 1
- 229940125693 central nervous system agent Drugs 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 210000002987 choroid plexus Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 201000006368 chronic pyelonephritis Diseases 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000006998 cognitive state Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010011005 corneal dystrophy Diseases 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 239000003997 corticotropin derivative Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 108010040063 dermatan sulfate proteoglycan Proteins 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- OMBRFUXPXNIUCZ-UHFFFAOYSA-N dioxidonitrogen(1+) Chemical compound O=[N+]=O OMBRFUXPXNIUCZ-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 125000005022 dithioester group Chemical group 0.000 description 1
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 1
- 239000002804 dopamine agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 108010018544 ebiratide Proteins 0.000 description 1
- 229950003546 ebiratide Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 102000034240 fibrous proteins Human genes 0.000 description 1
- 108091005899 fibrous proteins Proteins 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000017105 hereditary amyloidosis Diseases 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 150000002402 hexoses Chemical group 0.000 description 1
- 102000046783 human APP Human genes 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229940099552 hyaluronan Drugs 0.000 description 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 208000036260 idiopathic disease Diseases 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000021005 inheritance pattern Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000008449 language Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 150000008146 mannosides Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000004084 narcotic analgesic agent Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical compound C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- 125000001828 phenalenyl group Chemical group C1(C=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical class NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 125000005494 pyridonyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 108010033090 surfactant protein A receptor Proteins 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003553 thiiranes Chemical class 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000007944 thiolates Chemical group 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000001650 transport into the brain Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
- C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/69—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
- C07C381/02—Thiosulfates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/1651—Esters of thiophosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Definitions
- Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibrils.
- Amyloid is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefiingent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
- specific dyes e.g., Congo red
- Amyloid-related diseases can either be restricted to one organ or spread to several organs. The first instance is referred to as “localized amyloidosis” while the second is referred to as “systemic amyloidosis.”
- amyloid diseases can be idiopathic, but most of these diseases appear as a complication of a previously existing disorder.
- primary amyloidosis (AL amyloid) can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma.
- Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis).
- a familial form of secondary amyloidosis is also seen in other types of familial amyloidosis, e.g., Familial Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both primary and secondary amyloidosis, deposits are found in several organs and are thus considered systemic amyloid diseases.
- FMF Familial Mediterranean Fever
- “Localized amyloidoses” are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt- Jakob disease, and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by neuritic plaques and neurofibrillary tangles.
- amyloid plaques found in the parenchyma and the blood vessel is formed by the deposition of fibrillar A ⁇ amyloid protein.
- Other diseases such as adult-onset diabetes (type II diabetes) are characterized by the localized accumulation of amyloid fibrils in the pancreas.
- amyloids have formed, there is no known, widely accepted therapy or treatment which significantly dissolves amyloid deposits, in situ prevents further amyloid deposition or prevents the initiation of amyloid deposition.
- Each amyloidogenic protein has the ability to undergo a conformational change and to organize into ⁇ -sheets and form insoluble fibrils which may be deposited extracellularly or intracellularly.
- Each amyloidogenic protein although different in amino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and complement component.
- each amyloidogenic protein has amino acid sequences which, although different, show similarities such as regions with the ability to bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as the GAG binding site) as well as other regions which promote ⁇ -sheet formation.
- GAG glycosaminoglycan
- Proteoglycans are macromolecules of various sizes and structures that are districuted almost everywhere in the body.
- GAGs polysaccharide chains
- amyloid fibrils once deposited, can become toxic to the surrounding cells.
- the A ⁇ fibrils organized as senile plaques have been shown to be associated with dead neuronal cells, dystrophic neurites, astrocytosis, and micro gliosis in patients with Alzheimer's disease.
- oligomenc (soluble) as well as fibrillar A ⁇ peptide was shown to be capable of triggering an activation process of microglia (brain macrophages), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease. Both oligomeric and fibrillar A ⁇ peptide can also induce neuronal cell death in vitro.
- amyloidogenic protein IAPP when organized in oligomeric forms or in fibrils, has been shown to induce ⁇ -islet cell toxicity in vitro.
- appearance of LAPP fibrils in the pancreas of type II diabetic patients contributes to the loss of the ⁇ islet cells (Langerhans) and organ dysfunction which can lead to insulinemia.
- Another type of amyloidosis is related to ⁇ 2 microglobulin and is found in long- term hemodialysis patients. Patients undergoing long term hemodialysis will develop ⁇ 2 -microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in several joints. This causes severe pains, joint stiffness and swelling.
- Amyloidosis is also characteristic of Alzheimer's disease. Alzheimer's disease is a devastating disease of the brain that results in progressive memory loss leading to dementia, physical disability, and death over a relatively long period of time. With the aging populations in developed countries, the number of Alzheimer's patients is reaching epidemic proportions.
- amyloid or senile plaques surrounded by misshapen nerve terminals (dystrophic neurites) and activated microglia (microgliosis and astrocytosis).
- a main constituent of these amyloid plaques is the amyloid- ⁇ peptide (A ⁇ ), a 39-43 amino-acid protein that is produced through cleavage of the ⁇ -amyloid precursor protein (APP).
- a ⁇ Alzheimer's disease
- APP amyloid precursor protein
- ER endoplasmic reticulum
- Golgi apparatus or the endosomal-lysosomal pathway, and most is normally secreted as a 40 (“A ⁇ l-40") or 42 (“A ⁇ l-42”) amino acid peptide (Selkoe, Annu. Rev. Cell Biol. 10, 373-403 (1994)).
- a role for A ⁇ as a primary cause for Alzheimer's disease is supported by the presence of extracellular A ⁇ deposits in senile plaques of Alzheimer's disease, the increased production of A ⁇ in cells harboring mutant Alzheimer's disease associated genes, e.g. , amyloid precursor protein, presenilin I and presenilin II; and the toxicity of extracellular soluble (oligomeric) or fibrillar A ⁇ to cells in culture.
- mutant Alzheimer's disease associated genes e.g. , amyloid precursor protein, presenilin I and presenilin II
- extracellular soluble (oligomeric) or fibrillar A ⁇ to cells in culture.
- Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral angiopathy, and neurofibrillary tangles.
- Plaque and blood vessel amyloid is believed to be formed by the deposition of insoluble A ⁇ amyloid protein, which may be described as diffuse or fibrillary. Both soluble oligomeric A ⁇ and fibrillar A ⁇ are also believed to be neurotoxic and inflammatory.
- CAA cerebral amyloid angiopathy
- the present invention relates to the use of certain compounds in the treatment of amyloid-related diseases.
- the invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of a compound of the invention.
- the invention also pertains to each of the novel compounds of the invention as described herein.
- the compounds for use in the invention are those according to the following Formulae, such that, when administered, amyloid fibril formation, organ specific dysfunction (e.g., neurodegeneration), or cellular toxicity is reduced or inhibited.
- the invention pertains, at least in part to compounds of
- R 1 is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C 2 -C 10 alkyl group;
- R 2 is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
- X + is hydrogen, a cationic group, or an ester-forming group (i.e., as in a prodrug, which are described elsewhere herein); and each of L 1 and L 2 is independently a substituted or unsubstituted C1-C 5 alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R 1 is alkyl, L 1 is absent.
- the invention pertains, at least in part to compounds of Formula II:
- R 1 is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C 2 -C 10 alkyl group;
- R 2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked to R 1 to form a heterocycle;
- Y is SO 3 " X + , OSO 3 ⁇ X + , or SSOfX ⁇
- X 4* is hydrogen, a cationic group, or an ester forming moiety; m is 0 or 1; n is 1, 2, 3, or 4;
- L is substituted or unsubstituted C ⁇ -C 3 alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R 1 is alkyl, L is absent.
- the invention pertains, at least in part to compounds of Formula III:
- A is nitrogen or oxygen
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or 4; n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
- R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a is a moiety of Formula Ilia:
- m 0, 1, 2, 3, or 4;
- R ⁇ , R B , R , R D , and R E are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; and pharmaceutically acceptable salts and esters thereof, provided that said compound is not 3-(4-phenyl-l, 2, 3, 6-tetrahydro-l-pyridyl)-l-propanesulfonic acid.
- the invention pertains at least in part to compounds of Formula IN:
- A is nitrogen or oxygen;
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when
- A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or 4; n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
- R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R 4 and R 5 taken together, with the ring atoms they are attached to, form a double bond, or R and R taken together, with the ring atoms they are attached to, form a double bond; m is 0, 1, 2, 3, or 4;
- R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl, and pharmaceutically acceptable salts and esters thereof.
- the invention includes compounds of Formula V:
- A is nitrogen or oxygen
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
- x is 0, 1, 2, 3, or 4;
- n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
- aa is a natural or unnatural amino acid residue;
- m is 0, 1, 2, or 3;
- R 14 is hydrogen or protecting group
- R 15 is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and prodrugs thereof.
- the invention includes compounds of the Formula NI:
- n is i, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- A is oxygen or nitrogen;
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or 4;
- R 19 is hydrogen, alkyl or aryl
- Y 1 is oxygen, sulfur, or nitrogen
- Y 2 is carbon, nitrogen, or oxygen;
- R 20 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
- R 21 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent if Y 2 is oxygen;
- R 22 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or R 22 is hydrogen, hydroxyl, alkoxy or aryloxy if Y 1 is 00 1 00 O nitrogen; or R is absent if Y is oxygen or sulfur;or R and R may be linked to form a cyclic moiety if Y 1 is nitrogen;
- R 23 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or
- the compounds disclosed herein prevent or inhibit amyloid protein assembly into insoluble fibrils which, in vivo, are deposited in various organs, or it favors clearance of pre-formed deposits or slows deposition in patients already having deposits.
- the compound may also prevent the amyloid protein, in its soluble, oligomeric form or in its fibrillar form, from binding or adhering to a cell surface and causing cell damage or toxicity.
- the compound may block amyloid-induced cellular toxicity or macrophage activation.
- the compound may block amyloid-induced neurotoxicity or microglial activation.
- the compound protects cells from amyloid induced cytotoxicity of B-islet cells.
- the compound may enhance clearance from a specific organ, e.g., the brain or it decreases concentration of the amyloid protein in such a way that amyloid fibril formation is prevented in the targeted organ.
- the compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid fibril formation, aggregation or deposition.
- the compounds of the invention may act to ameliorate the course of an amyloid related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid; or favoring the degradation of amyloid protein prior to its organization in fibrils.
- the compounds of the invention maybe administered therapeutically or prophylactically to treat diseases associated with amyloid- ⁇ fibril formation, aggregation or deposition.
- the compounds of the invention may act to ameliorate the course of an amyloid- ⁇ related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid- ⁇ fibril formation or deposition; lessening the degree of amyloid- ⁇ deposition; inhibiting, reducing, or preventing amyloid- ⁇ fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid- ⁇ ; inhibiting amyloid- ⁇ induced inflammation; enhancing the clearance of amyloid- ⁇ from the brain; or favoring the degradation of amyloid- ⁇ protein prior to its organization in fibrils.
- Therapeutic compounds of the invention may be effective in controlling amyloid- ⁇ deposition either following their entry into the brain (following penetration of the blood brain barrier) or from the periphery.
- a compound When acting from the periphery, a compound may alter the equilibrium of A/3 between the brain and the plasma so as to favor the exit of A/3 from the brain. It may also increase the catabolism of neuronal A/3 and change the rate of exit from the brain. An increase in the exit of A ⁇ from the brain would result in a decrease in A/3 brain and cerebrospinal fluid (CSF) concentration and therefore favor a decrease in A/3 deposition.
- CSF cerebrospinal fluid
- compounds that penetrate the brain could control deposition by acting directly on brain A ⁇ e.g., by maintaining it in a non-fibrillar form, favoring its clearance from the brain, or by slowing down APP processing. These compounds could also prevent A ⁇ in the brain from interacting with the cell surface and therefore prevent neurotoxicity, neurodegeneration or inflammation. They may also decrease A ⁇ production by activated microglia. The compounds may also increase degradation by macrophages or neuronal cells.
- the method is used to treat Alzheimer's disease (e.g., sporadic, familial, or early AD).
- the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”) or hereditary cerebral hemorrhage.
- CAA cerebral amyloid angiopathy
- the method is used to treat mild cognitive impairment.
- Mild Cognitive Impairment is a condition characterized by a state of mild but measurable impairment in flunking skills, which is not necessarily associated with the presence of dementia. MCI frequently, but not necessarily, precedes Alzheimer's disease.
- the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which amyloid-beta protein is abnormally deposited at non-neurological locations, such as treatment of IBM by delivery of the compounds to muscle fibers.
- a ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium in individuals with age-related macular degeneration (AMD). AMD is a cause of irreversible vision loss in older individuals. It is believed that A ⁇ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD (Johnson, etal, Proc. Natl. Acad. Sci. USA 99(18), 11830-5 (2002)).
- the present invention therefore relates to the use of compounds of Formulae I, II, HI, IN, N, NI, or otherwise described herein in the prevention or treatment of amyloid- related diseases, including, inter alia, Alzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment, inclusion body myositis, Down's syndrome, macular degeneration, as well as other types of amyloidosis like LAPP- related amyloidosis (e.g., diabetes), primary (AL) amyloidosis, secondary (AA) amyloidosis and ⁇ 2 microglobulin-related (dialysis-related) amyloidosis.
- amyloid- related diseases including, inter alia, Alzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment, inclusion body myositis, Down's syndrome, macular degeneration, as well as other types of amyloidosis like LAPP- related amyloidosis (e.g., diabetes), primary (AL) amyloido
- LAPP Type II diabetes related amyloidosis
- the amyloidogenic protein LAPP induces ⁇ -islet cell toxicity when organized in oligomeric forms or in fibrils.
- appearance of LAPP fibrils in the pancreas of type II diabetic patients contributes to the loss of the ⁇ islet cells (Langerhans) and organ dysfunction which leads to insulinemia.
- a amyloid Primary amyloidosis (AL amyloid) is usually found associated with plasma cell dyscrasia and multiple myeloma. It can also be found as an idiopathic disease.
- AA amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis).
- a familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF).
- FMF Familial Mediterranean Fever
- ⁇ 2 microglobulin-related (dialysis-related) amyloidosis is found in long-term hemodialysis patients. Patients undergoing long term hemodialysis will develop ⁇ - microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in several joints. This causes severe pains, joint stiffness and swelling. These deposits are due to the inability to maintain low levels of /3 2 M in plasma of dialyzed patients. Increased plasma concentrations of ⁇ 2 M protein will induce structural changes and may lead to the deposition of modified /3 2 M as insoluble fibrils in the joints.
- the present invention relates to the use of compounds of Formulae I, II, III, JN, N, NI, or compounds otherwise described herein in the treatment of amyloid-related diseases.
- amyloid-Related Diseases For convenience, some definitions of terms referred to herein are set forth below.
- AA amyloidosis is a manifestation of a number of diseases that provoke a sustained acute phase response. Such diseases include chronic inflammatory disorders, chronic local or systemic microbial infections, and malignant neoplasms. The most common form of reactive or secondary (AA) amyloidosis is seen as the result of long-standing inflammatory conditions. For example, patients with Rheumatoid Arthritis or Familial Mediterranean Fever (which is a genetic disease) can develop AA amyloidosis.
- Rheumatoid Arthritis or Familial Mediterranean Fever which is a genetic disease
- Familial Mediterranean Fever which is a genetic disease
- AA fibrils are generally composed of 8,000 Dalton fragments (AA peptide or protein) formed by proteolytic cleavage of serum amyloid A protein (ApoSAA), a circulating apolipoprotein which is mainly synthesized in hepatocytes in response to such cytokines as IL-1, IL-6 and TNF. Once secreted, ApoSAA is complexed with HDL. Deposition of AA fibrils can be widespread in the body, with a preference for parenchymal organs. The kidneys are usually a deposition site, and the liver and the spleen may also be affected. Deposition is also seen in the heart, gastrointestinal tract, and the skin.
- ApoSAA serum amyloid A protein
- AA amyloidosis Underlying diseases which can lead to the development of AA amyloidosis include, but are not limited to inflammatory diseases, such as rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's syndrome, Adult Still's disease, Behcet's syndrome, and Crohn's disease.
- AA deposits are also produced as a result of chronic microbial infections, such as leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, and Whipple's disease.
- Certain malignant neoplasms can also result in AA fibril amyloid deposits. These include such conditions as Hodgkin's lymphoma, renal carcinoma, carcinomas of gut, lung and urogenital tract, basal cell carcinoma, and hairy cell leukemia. Other underlying conditions that may be associated with AA amyloidosis are Castleman's disease and Schnitzler's syndrome. AL Amyloidoses (Primary Amyloidosis)
- AL amyloid deposition is generally associated with almost any dyscrasia of the B lymphocyte lineage, ranging from malignancy of plasma cells (multiple myeloma) to benign monoclonal gammopathy. At times, the presence of amyloid deposits may be a primary indicator of the underlying dyscrasia. AL amyloidosis is also described in detail in Current Drug Targets, 2004, 5 159-171. Fibrils of AL amyloid deposits are composed of monoclonal immunoglobulin light chains or fragments thereof. More specifically, the fragments are derived from the N-terminal region of the light chain (kappa or lambda) and contain all or part of the variable (V L ) domain thereof.
- Deposits generally occur in the mesenchymal tissues, causing peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasias, myelomas, as well as occult dyscrasias.
- tissue particularly visceral organs such as the kidney, liver, spleen and heart, may be involved.
- Hereditary Systemic Amyloidoses There are many forms of hereditary systemic amyloidoses. Although they are relatively rare conditions, adult onset of symptoms and their inheritance patterns (usually autosomal dominant) lead to persistence of such disorders in the general population. Generally, the syndromes are attributable to point mutations in the precursor protein leading to production of variant amyloidogenic peptides or proteins. Table 1 summarizes the fibril composition of exemplary forms of these disorders.
- Table 1 The data provided in Table 1 are exemplary and are not intended to limit the scope of the invention. For example, more than 40 separate point mutations in the transthyretin gene have been described, all of which give rise to clinically similar forms of familial amyloid polyneuropathy.
- any hereditary amyloid disorder can also occur sporadically, and both hereditary and sporadic forms of a disease present with the same characteristics with regard to amyloid.
- the most prevalent form of secondary AA amyloidosis occurs sporadically, e.g. as a result of ongoing inflammation, and is not associated with Familial Mediterranean Fever.
- general discussion relating to hereditary amyloid disorders below can also be applied to sporadic amyloidoses.
- Transthyretin is a 14 kiloDalton protein that is also sometimes referred to as prealbumin. It is produced by the liver and choroid plexus, and it functions in transporting thyroid hormones and vitamin A. At least 50 variant forms of the protein, each characterized by a single amino acid change, are responsible for various forms of familial amyloid polyneuropathy. For example, substitution of proline for leucine at position 55 results in a particularly progressive form of neuropathy; substitution of metliionine for leucine at position 111 resulted in a severe cardiopathy in Danish patients.
- ATTR fibril components can be extracted from such plaques and their structure and sequence determined according to the methods known in the art (e.g., Gustavsson, A., et al, Laboratory Invest. 73: 703-708, 1995; Kametani, F., et al, Biochem. Biophys. Res. Commun. 125: 622-628, 1984; Pras, M., et al, PNAS 80: 539-42, 1983). Persons having point mutations in the molecule apolipoprotein Al (e.g.,
- Gly-»Arg26; Trp— Arg50; Leu— »Arg60 exhibit a form of amyloidosis ("Ostertag type") characterized by deposits of the protein apolipoprotein Al or fragments thereof (AApoAI). These patients have low levels of high density lipoprotein (HDL) and present with a peripheral neuropathy or renal failure.
- a mutation in the alpha chain of the enzyme lysozyme e.g., Ile- ⁇ -Thr56 or
- Asp-»His57 is the basis of another form of Ostertag-type non-neuropathic hereditary amyloid reported in English families.
- fibrils of the mutant lysozyme protein (Alys) are deposited, and patients generally exhibit impaired renal function.
- This protein unlike most of the fibril-forming proteins described herein, is usually present in whole (unfragmented) form (Benson, M.D., et al. CLBA Fdn. Symp. 199: 104-131, 1996).
- Lmmxmoglobulin light chains tend to form aggregates in various morphologies, including fibrillar (e.g., AL amyloidosis and AH amyloidosis), granular (e.g., light chain deposition disease (LCDD), heavy chain deposition disease (HCDD), and light-heavy chain deposition disease (LHCDD)), crystalline (e.g., Acquired Farconi's Syndome), . and microtubular (e.g., Cryoglobulinemia).
- fibrillar e.g., AL amyloidosis and AH amyloidosis
- granular e.g., light chain deposition disease (LCDD), heavy chain deposition disease (HCDD), and light-heavy chain deposition disease (LHCDD)
- crystalline e.g., Acquired Farconi's Syndome
- microtubular e.g., Cryoglobulinemia
- ⁇ chains such as ⁇ NI chains ( ⁇ 6 chains)
- K chains kappa chains
- ⁇ LTI chains are also slightly elevated.
- Merlini et al CLIN CHEM LAB MED 39(11): 1065-75 (2001).
- Heavy chain amyloidosis (AH) is generally characterized by aggregates of gamma chain amyloid proteins of the IgGl subclass. Eulitz et al, PROC NATL ACAD SCI USA 87:6542-46 (1990).
- AL and LCDD have been distinguished from other amyloid diseases due to their relatively small population monoclonal light chains, which are manufactured by neoplastic expansion of an antibody-producing B cell.
- AL aggregates typically are well-ordered fibrils of lambda chains.
- LCDD aggregates are relatively amorphous aggregations of both kappa and lambda chains, with
- amloidogenic heavy chain characterized as consisting solely of the NH-D portion of the non-amyloidogenic heavy chain.
- potential methods of detecting and monitoring treatment of subjects having or at risk of having AL, LCDD, AH, and the like include but are not limited to immunoassaying plasma or urine for the presence or depressed deposition of amyloidogenic light or heavy chains, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ IN, amyloid ⁇ , or amyloid I .
- Brain Amyloidosis The most frequent type of amyloid in the brain is composed primarily of
- Brain amyloidosis includes those diseases, conditions, pathologies, and other abnormalities of the structure or function of the brain, including components thereof, in which the causative agent is amyloid.
- the area of the brain affected in an amyloid-related disease may be the stroma including the vasculature or the parenchyma including functional or anatomical regions, or neurons themselves.
- a subject need not have received a definitive diagnosis of a specifically recognized amyloid-related disease.
- the term "amyloid related disease” includes brain amyloidosis.
- Amyloid- ⁇ peptide is a 39-43 amino acid peptide derived by proteolysis from a large protein known as Beta Amyloid Precursor Protein (“ ⁇ APP"). Mutations in ⁇ APP result in familial forms of Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, and senile dementia, characterized by cerebral deposition of plaques composed of A ⁇ fibrils and other components, which are described in further detail below.
- APP Amyloid Precursor Protein
- position 717 is proximate to the site of gamma-secretase cleavage of APP in its processing to A ⁇
- positions 670/671 are proximate to the site of ⁇ -secretase cleavage. Mutations at any of these residues may result in Alzheimer's disease, presumably by causing an increase in the amount of the 42/43 amino acid form of A ⁇ generated from APP.
- the familial form of Alzheimer's disease represents only 10% of the subject population. Most occurrences of Alzheimer's disease are sporadic cases where APP and A ⁇ do not possess any mutation.
- the structure and sequence of A ⁇ peptides of various lengths are well known in the art.
- Such peptides can be made according to methods known in the art, or extracted from the brain according to known methods (e.g., Glenner and Wong, Biochem. Biophys. Res. Comm. 129, 885-90 (1984); Glenner and Wong, Biochem.
- APP is expressed and constitutively catabolized in most cells.
- the dominant catabolic pathway appears to be cleavage of APP within the A ⁇ sequence by an enzyme provisionally termed c-secretase, leading to release of a soluble ectodomain fragment known as APPsc . This cleavage precludes the fonnation of A ⁇ peptide.
- APP can also be cleaved by enzymes known as ⁇ - and ⁇ -secretase at the N- and C-termini of the A ⁇ , respectively, followed by release of A ⁇ into the extracellular space.
- BACE has been identified as ⁇ -secretase (Nasser, et al, Science 286:735-741, 1999) and presenilins have been implicated in 7-secretase activity (De Strooper, et al, Nature 391, 387-90 (1998)).
- the 39-43 amino acid A ⁇ peptide is produced by sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ⁇ and 7 secretases enzyme.
- a ⁇ 40 is the predominant form produced, 5-7% of total A ⁇ exists as A ⁇ 42 (Cappai et al, Int. J. Biochem. Cell Biol. 31. 885-89 (1999)).
- a ⁇ peptide appears to dramatically alter its biochemical/biophysical properties. Specifically, the additional two amino acids at the C-terminus of A ⁇ 42 are very hydrophobic, presumably increasing the propensity of A ⁇ 42 to aggregate.
- Jarrett, et al. demonstrated that A ⁇ 42 aggregates very rapidly in vitro compared to A ⁇ 40, suggesting that the longer forms of A ⁇ may be the important pathological proteins that are involved in the initial seeding of the neuritic plaques in Alzheimer's disease (Jarrett, et al, Biochemistry 32, 4693-97 (1993); Jarrett, et al, Ann. N. Y. Acad. Sci. 695, 144-48 (1993)).
- Presenilin-1 Presenilin-1
- PS2 Presenilin-2
- CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I); the Dutch variant of HCHWA (HCHWA-D; a mutation in A/3); the Flemish mutation of A ⁇ ; the Arctic mutation of A/3; the Italian mutation of A/3; the Iowa mutation of A/3; familial British dementia; and familial Danish dementia.
- CAA may also be sporadic.
- ⁇ amyloid As used herein, the terms “ ⁇ amyloid,” “amyloid- ⁇ ,” and the like refer to amyloid ⁇ proteins or peptides, amyloid ⁇ precursor proteins or peptides, intermediates, and modifications and fragments thereof, unless otherwise specifically indicated.
- a ⁇ refers to any peptide produced by proteolytic processing of the APP gene product, especially peptides which are associated with amyloid pathologies, including A ⁇ l-39, A ⁇ l-40, A ⁇ l-41, A ⁇ l-42, and A ⁇ l-43.
- A/31-42 maybe referred to herein as “A/3(l-42)” or simply as “A/342” or “A/3 42 “ (and likewise for any other amyloid peptides discussed herein).
- ⁇ amyloid As used herein, the terms “ ⁇ amyloid,” “amyloid-/3,” and “A ⁇ ” are synonymous.
- the term “amyloid” refers to amyloidogenic proteins, peptides, or fragments thereof which can be soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having fibrillary structure or in amyloid plaque). See, e.g., MP Lambert, et al, Proc. Nat'lAcad. Sci.
- Amyloidosis or "amyloid disease” or “amyloid-related disease” refers to a pathological condition characterized by the presence of amyloid fibers.
- Amyloid is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefiingent appearance in polarized light after staining. They also share common ulfrastructural features and common X-ray diffraction and infrared spectra.
- Gelsolin is a calcium binding protein that binds to fragments and actin filaments. Mutations at position 187 (e.g., Asp-»Asn; Asp-»Tyr) of the protein result in a form of hereditary systemic amyloidosis, usually found in patients from Finland, as well as persons of Dutch or Japanese origin. In afflicted individuals, fibrils formed from gelsolin fragments (Agel), usually consist of amino acids 173-243 (68 kDa carboxyterminal fragment) and are deposited in blood vessels and basement membranes, resulting in corneal dystrophy and cranial neuropathy which progresses to peripheral neuropathy, dystrophic skin changes and deposition in other organs. (Kangas, H., et al. Human Mol. Genet. 5(9): 1237-1243, 1996).
- mutant alpha chain of fibrinogen (AfibA) and mutant cystatin C (Acys) also form fibrils and produce characteristic hereditary disorders.
- AfibA fibrils form deposits characteristic of a nonneuropathic hereditary amyloid with renal disease; Acys deposits are characteristic of a hereditary cerebral amyloid angiopathy reported in Iceland (Isselbacher, Harrison's Principles of Internal Medicine, McGraw-Hill, San Francisco, 1995; Benson, et al).
- CAA cerebral amyloid angiopathy
- PrP Sc abnormal isoforms of the normal prion protein
- AScr A predominant mutant isoform, PrP Sc , also referred to as AScr, differs from the normal cellular protein in its resistance to protease degradation, insolubility after detergent extraction, deposition in secondary lysosomes, post-translational synthesis, and high ⁇ -pleated sheet content.
- CJD Creutzfeldt- Jacob disease
- GSS Gerstmann-Sfraussler-Scheinker syndrome
- FFI fatal familial insomnia
- GSS has been linked to a PrP mutation at codon 102, while telencephalic GSS segregates with a mutation at codon 117. Mutations at codons 198 and 217 result in a form of GSS in which neuritic plaques characteristic of
- Alzheimer's disease contain PrP instead of A ⁇ peptide.
- Certain forms of familial CJD have been associated with mutations at codons 200 and 210; mutations at codons 129 and 178 have been found in both familial CJD and FFI. (Baldwin, supra).
- Cerebral Amyloidosis Local deposition of amyloid is common in the brain, particularly in elderly individuals. The most frequent type of amyloid in the brain is composed primarily of A/3 peptide fibrils, resulting in dementia or sporadic (non-hereditary) Alzheimer's disease. The most common occurrences of cerebral amyloidosis are sporadic and not familial. For example, the incidence of sporadic Alzheimer's disease and sporadic CAA greatly exceeds the incidence of familial AD and CAA.
- Cerebral amyloid angiopathy refers to the specific deposition of amyloid fibrils in the walls of leptomingeal and cortical arteries, arterioles and veins. It is commonly associated with Alzheimer's disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke or dementia (see Frangione et al, Amyloid: J. Protein Folding Disord. 8, Suppl. 1, .36-42 (2001)). CAA can occur sporadically or be hereditary. Senile Systemic Amyloidosis
- Amyloid deposition increases with age. For example, fibrils of wild type transthyretin (TTR) are commonly found in the heart tissue of elderly individuals. These may be asymptomatic, clinically silent, or may result in heart failure. Asymptomatic fibrillar focal deposits may also occur in the brain (A ⁇ ), corpora amylacea of the prostate (/3 2 microglobulin), joints and seminal vesicles.
- TTR transthyretin
- DAA Dialysis-related Amyloidosis
- ⁇ microglobulin ( 3 M) fibrils commonly develop in patients receiving long term hemodialysis or peritoneal dialysis.
- ⁇ 2 microglobulin is a 11.8 kiloDalton polypeptide and is the light chain of Class I MHC antigens, which are present on all nucleated cells.
- /3 2 M is usually distributed in the extracellular space unless there is an impaired renal function, in which case /3 2 M is transported into tissues where it polymerizes to form amyloid fibrils. Failure of clearance such as in the case of impaired renal function, leads to deposition in the carpal tunnel and other sites (primarily in collagen-rich tissues of the joints).
- /3 2 M molecules are not produced by cleavage of a longer precursor protein and are generally present in unfragmented form in the fibrils. (Benson, supra). Retention and accumulation of this amyloid precursor has been shown to be the main pathogenic process underlying DRA.
- DRA is characterized by peripheral joint osteoarthropathy (e.g., joint stiffness, pain, swelling, etc.). Isoforms of /3 M, glycated /3 2 M, or polymers of /3 2 M in tissue are the most amyloidogenic form (as opposed to native /3 2 M). Unlike other types of amyloidosis, /3 2 M is confined largely to osteoarticular sites. Visceral depositions are rare.
- Islet Amyloid Polypeptide and Diabetes Islet hyalinosis was first described over a century ago as the presence of fibrous protein aggregates in the pancreas of patients with severe hyperglycemia (Opie, EL., JExp. Med. 5: 397-428, 1901).
- islet amyloid composed predominantly of islet amyloid polypeptide (LAPP), or amylin
- LAPP islet amyloid polypeptide
- NIDDM Non-Insulin Dependent Diabetes
- LAPP is co-secreted with insulin in response to ⁇ -cell secretagogues.
- This pathological feature is not associated with insulin-dependent (Type I) diabetes and is a unifying characteristic for the heterogeneous clinical phenotypes diagnosed as NIDDM (Type II diabetes).
- LAPP has also been shown to induce ⁇ -islet cell toxicity in vitro, indicating that appearance of LAPP fibrils in the pancreas of Type II or Type I diabetic patients (post-islet transplantation) could contribute to the loss of the ⁇ -cell islets (Langerhans) and organ dysfunction.
- pancreatic LAPP leads to formation of oligomeric IAPP, leading to a buildup of IAPP-amyloid as insoluble fibrous deposits which eventually destroys the insulin-producing ⁇ cells of the islet, resulting in ⁇ cell depletion and failure (Westermark, P., Grimelius, L., Acta Path. Microbiol Scand., sect. A. 81: 291-300,
- LAPP fibrils are likely to continue to grow after the cells are transplanted and cause death or dysfunction of the cells. This may occur even when the cells are from a healthy donor and the patient receiving the transplant does not have a disease that is characterized by the presence of fibrils.
- compounds of the present invention may also be used in preparing tissues or cells for transplantation according to the methods described in International Patent Application (PCT) number WO 01/003680.
- the compounds of the invention may also stabilize the ratio of the concentrations of Pro-LAPP/LAPP, pro-Insulin/Insulin and C-peptide levels.
- the results of the different tests such as the arginine-insulin secretion test, the glucose tolerance test, insulin tolerance and sensitivity tests, could all be used as markers of reduced ⁇ -cell mass and/or accumulation of amyloid deposits.
- Such class of drugs could be used together with other drugs targeting insulin resistance, hepatic glucose production, and insulin secretion.
- Such compounds might prevent insulin therapy by preserving ⁇ -cell function and be applicable to preserving islet transplants.
- Endocrine organs may harbor amyloid deposits, particularly in aged individuals.
- Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the fibrils of which are made up of polypeptide hormones such as calcitonin (medullary carcinoma of the thyroid), and atrial natriuretic peptide (isolated atrial amyloidosis). Sequences and structures of these proteins are well known in the art.
- amyloid disease There are a variety of other forms of amyloid disease that are normally manifest as localized deposits of amyloid. Ln general, these diseases are probably the result of the localized production or lack of catabolism of specific fibril precursors or a predisposition of a particular tissue (such as the joint) for fibril deposition. Examples of such idiopathic deposition include nodular AL amyloid, cutaneous amyloid, endocrine amyloid, and tumor-related amyloid.
- amyloid related diseases include those described in Table 1, such as familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, Tenosynovium, familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis , familial Creutzfeldt- Jakob disease; Gerstmann-Straussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle-Well's syndrome, nephropathy, deafness, urticaria, limb pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated amyloidosis, medullary carcinomas of the thyroid, isolated atrial amyloid, and diabetes.
- FAP familial amy
- the compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid fibril formation, aggregation or deposition, regardless of the clinical setting.
- the compounds of the invention may act to ameliorate the course of an amyloid related disease using any of the following mechanisms, such as, for example but not limited to: slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid from, for example, the brain; or protecting cells from amyloid induced (oligomers or fibrillar) toxicity.
- the compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid- ⁇ fibril formation, aggregation or deposition.
- the compounds of the invention may act to ameliorate the course of an amyloid- ⁇ related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid- ⁇ fibril formation or deposition; lessening the degree of amyloid- ⁇ deposition; inhibiting, reducing, or preventing amyloid- ⁇ fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid- ⁇ ; inhibiting amyloid- ⁇ induced inflammation; enhancing the clearance of amyloid- ⁇ from the brain; or favoring greater catabolism of A/3.
- Compounds of the invention may be effective in controlling amyloid- ⁇ deposition either following their entry into the brain (following penetration of the blood brain barrier) or from the periphery.
- a compound When acting from the periphery, a compound may alter the equilibrium of A/3 between the brain and the plasma so as to favor the exit of A/3 from the brain.
- An increase in the exit of A/3 from the brain would result in a decrease in A ⁇ brain concentration and therefore favor a decrease in A/3 deposition
- compounds that penetrate the brain may control deposition by acting directly on brain A ⁇ , e.g. , by maintaining it in a non-fibrillar form or favoring its clearance from the brain.
- the compounds may slow down APP processing; may increase degradation of A ⁇ fibrils by macrophages or by neuronal cells; or may decrease A/3 production by activated microglia. These compounds could also prevent A ⁇ in the brain from interacting with the cell surface and therefore prevent neurotoxicity, neurodegeneration, or inflammation.
- the method is used to treat Alzheimer's disease (e.g., sporadic or familial AD).
- the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”), hereditary cerebral hemorrhage, or early Alzheimer's disease.
- CAA cerebral amyloid angiopathy
- the method is used to treat mild cognitive impairment. Mild Cognitive Impairment (“MCI”) is a condition characterized by a state of mild but measurable impairment in thinking skills, which is not necessarily associated with the presence of dementia. MCI frequently, but not necessarily, precedes Alzheimer's disease.
- the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which amyloid-beta protein is abnonnally deposited at non-neurological locations, such as treatment of LBM by delivery of the compounds to muscle fibers.
- a ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium in individuals with age-related macular degeneration (ARMD).
- ARMD is a cause of irreversible vision loss in older individuals. It is believed that A ⁇ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of ARMD (Johnson, et al, Proc. ⁇ atl. Acad. Sci. USA 99(18), 11830-5 (2002)).
- the invention also relates to amethod of treating or preventing an amyloid-related disease in a subject (preferably a human) comprising administering to the subject a therapeutic amount of a compound according to the following Formulae or otherwise described herein, such that amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited.
- the invention in another embodiment, relates to a method of treating or preventing an amyloid- related disease in a subject (preferably a human) comprising administering to the subject a therapeutic amount of a compound according to the following Formulae or otherwise described herein, such that cognitive function is improved or stabilized or further deterioration in cognitive function is prevented, slowed, or stopped in patients with brain amyloidosis, e.g., Alzheimer's disease, Down's syndrome or cerebral amyloid angiopathy.
- brain amyloidosis e.g., Alzheimer's disease, Down's syndrome or cerebral amyloid angiopathy.
- the therapeutic compounds of the invention may treat amyloidosis related to type II diabetes by, for example, stabilizing glycemia, preventing or reducing the loss of ⁇ cell mass, reducing or preventing hyperglycemia due to loss of ⁇ cell mass, and modulating (e.g., increasing or stabilizing) insulin production.
- the compounds of the invention may also stabilize the ratio of the concentrations of pro-IAPP/IAPP.
- the therapeutic compounds of the invention may treat AA (secondary) amyloidosis and/or AL (primary) amyloidosis, by stabilizing renal function, decreasing proteinuria, increasing creatinine clearance (e.g., by at least 50% or greater or by at least 100% or greater), by leading to remission of chronic diarrhea or weight gain (e.g., 10% or greater), reducing serum creatinine, or reducing visceral amyloid content as determined, e.g., by SAP scinitigraphy.
- AA secondary amyloidosis
- AL primary amyloidosis
- the present invention relates, at least in part, to the use of certain chemical compounds (and pharmaceutical formulations thereof) in the prevention or treatment of amyloid-related diseases, including, inter alia, Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, diabetes related amyloidosis, hemodialysis-related amyloidosis (/3 2 M), primary amyloidosis (e.g., ⁇ or K chain- related), familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, familial amyloidosis, Ostertag-type non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial Creutzfeldt- Jakob disease, Gerstmann-Straussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle- Well's syndrome,
- alkenes can include either the E- or Z- geometry, where appropriate.
- the compounds of the present invention may exist in unsolvated as well as solvated forms with acceptable solvents such as water, THF, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
- a "small molecule” refers to a compound that is not itself the product of gene transcription or translation (e.g., protein, RNA, or DNA) and preferably has a low molecular weight, e.g., less than about 2500 amu.
- nucleophile is art-recognized to mean a chemical group having a reactive pair of electrons that reacts with a compound by displacing a leaving group (commonly another nucleophile), such as commonly occur in aliphatic chemistry as unimolecular (known as "S N I") or bimolecular (“S N 2") reactions.
- nucleophiles include uncharged compounds such as amines, mercaptans, and alcohols, and charged groups such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
- Illustrative anionic nucleophiles include, ter alia, simple anions such as azide, cyanide, thiocyanate, acetate, formate, or chloroformate, and bisulfite.
- Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, and acetylides, will under appropriate reaction conditions, be suitable nucleophiles.
- an "electrophile” means an atom, molecule, or ion able to accept an electron pair, particularly a pair of electrons from a nucleophile, such as typically occurs during an electrophilic substitution reaction.
- an electrophile binds to a substrate with the expulsion of another electrophile, e.g., the substitution of a proton by another electrophile such as a nitronium ion on an aromatic substrate (e.g., benzene).
- Electrophiles include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, and lactams; and non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, and iodides.
- an electrophile may be a saturated carbon atom (e.g., a methylene group) bonded to a leaving group; however, an electrophile may also be an unsaturated group, such as an aldehyde, ketone, ester, or conjugated ( ⁇ , 3-unsaturated) analog thereof, which upon reaction with a nucleophile forms an adduct.
- the term "leaving group” generally refers to a group that is readily displaced and substituted by a nucleophile (e.g., an amine, a thiol, an alcohol, or cyanide).
- Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide (" ⁇ HS”), N-hydroxybenzotriazole, a halogen (fluorine, chlorine, bromine, or iodine), alkoxides, and thioalkoxides.
- alkane sulfonyloxy groups e.g., C ⁇ -C alkane such as methane sulfonyloxy, ethane sulfonyloxy, propane sulfonyloxy, and butane sulfonyloxy groups
- halogenated analogs e.g., halogeno(C 1 -C alkane) sulfonyloxy groups, such as trifluoromethane sulfonyloxy (i.e., triflate), 2,2,2-trichloroethane sulfonyloxy, 3,3,3-tribromopropane sulfonyloxy, and
- 4,4,4-trifluorobutane sulfonyloxy groups 4,4,4-trifluorobutane sulfonyloxy groups
- arylsulfonyloxy groups e.g., C 6 -C ⁇ o aryl optionally substituted with 1 to 3 C ⁇ -C 4 alkyl groups, such as benzene sulfonyloxy, ⁇ -naphthylsulfonyloxy, /3-naphthylsulfonyloxy, -toluenesulfonyloxy (i.e., tosylates), 4-tert-butylbenzene sulfonyloxy, mesitylene sulfonyloxy, and 6-ethyl- c-naphthylsulfonyloxy groups) .
- Activated esters may be represented by the formula -COL, where L is a leaving group, typical examples of which include N-hydroxysulfosuccinimidyl and N-hydroxysuccinimidyl groups; aryloxy groups substituted with electron-withdrawing groups (e.g., /?-nitro, pentafluoro, pentachloro, -cyano, or -trifluoromethyl); and carboxylic acids activated by a carbodiimide to form an anhydride or mixed anhydride, e.g., -OCOR a or -OC ⁇ R a ⁇ HR b , where R a and R b are independently C ⁇ -C 6 alkyl, C 5 -C 8 alkyl (e.g., cyclohexyl), C ⁇ -C 6 perfluoroalkyl, or C ⁇ -C 6 alkoxy groups.
- L is a leaving group, typical examples of which include N-hydroxysulfosuccinimid
- An activated ester may be formed in situ or may be an isolable reagent.
- Sulfosuccinimidyl esters, pentafluorothiophenol esters, and sulfotetrafluorophenol are preferred activated esters.
- ester leaving group maybe, for example, substituted or unsubstituted C ⁇ -C 6 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl), or substituted or unsubstituted C 6 -C 1 aryl or heterocyclic groups, such as 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dibromoethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-chlorobutyl, methoxymethyl, 1,1 -dimethyl- 1 -methoxymethyl, ethoxymethyl, N-propoxymethyl, isopropoxymethyl, N-butoxymethyl, tert-butoxymethyl, 1-ethoxyethyl, 1 -methyl- 1-methoxyethyl,
- the term "electron-withdrawing group” is art-recognized and describes the ability of a substituent to attract valence electrons (e.g., pi-electrons) from neighboring atoms, e.g., the substituent is more electronegative than neighboring atoms, or it draws electrons to itself more than a hydrogen atom would at the same position.
- the Hammett sigma value ( ⁇ ) is an accepted measure of a group's electron-donating and withdrawing ability, especially the sigma para value ( ⁇ p ). See, e.g., "Advanced Organic Chemistry” by J. March, 5 th Ed., John Wiley & Sons, Inc., New York, pp.368-75 (2001).
- Exemplary electron-withdrawing groups include nitro, acyl (ketone), formyl (aldehyde), sulfonyl, trifluoromethyl, halogeno (e.g., cl ⁇ loro and fluoro), and cyano groups, among others.
- an "electron-donating group” designates a substituent that contributes electrons more than hydrogen would if it occupied the same position in the molecule. Examples include amino (including alkylamino and dialkylamino), aryl, alkoxy (including aralkoxy), aryloxy, mercapto and alkylthio, and hydroxyl groups, among others.
- alkyl groups include saturated hydrocarbons having one or more carbon atoms, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), cyclic alkyl groups (or “cycloalkyl” or “alicyclic” or “carbocyclic” groups) (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkyl groups (e.g., alkyl-substituted cycloalkyl groups and cycloalkyl-
- aliphatic group includes organic moieties characterized by straight or branched-chains, typically having between 1 and 22 carbon atoms. Ln complex structures, the chains may be branched, bridged, or cross-linked. Aliphatic groups include alkyl groups, alkenyl groups, and alkynyl groups. h certain embodiments, a straight-chain or branched-chain alkyl group may have 30 or fewer carbon atoms in its backbone, e.g., C ⁇ -C 3 o for straight-chain or C 3 -C 30 for branched-chain.
- a straight-chain or branched-chain alkyl group may have 20 or fewer carbon atoms in its backbone, e.g., C ⁇ -C 20 for straight-chain or C 3 -C 20 for branched-chain, and more preferably 18 or fewer.
- preferred cycloalkyl groups have from 4-10 carbon atoms in their ring structure, and more preferably have 4-7 carbon atoms in the ring structure.
- lower alkyl refers to alkyl groups having from 1 to 6 carbons in the chain, and to cycloalkyl groups having from 3 to 6 carbons in the ring structure.
- lower as in “lower aliphatic,” “lower alkyl,” “lower alkenyl,” etc. as used herein means that the moiety has at least one and less than about 8 carbon atoms.
- a straight-chain or branched-chain lower alkyl group has 6 or fewer carbon atoms in its backbone (e.g., C ⁇ -C 6 for straight-chain, C 3 -C 6 for branched-chain), and more preferably 4 or fewer.
- preferred cycloalkyl groups have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
- C ⁇ -C 6 as in "C ⁇ -C 6 alkyl” means alkyl groups containing 1 to 6 carbon atoms.
- alkyl includes both "unsubstituted alkyls" and “substituted alkyls,” the latter of which refers to alkyl groups having substituents replacing one or more hydrogens on one or more carbons of the hydrocarbon backbone.
- substituents may include, for example, alkenyl, alkynyl, halogeno, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
- alkylaryl moiety is an aryl group substituted with an alkyl group (e.g., -methylphenyl (i.e.,p-to ⁇ y ⁇ )).
- n-alkyl means a straight-chain (i.e., unbranched) iinsubstituted alkyl group.
- alkylene is a divalent analog of the corresponding alkyl group.
- alkenyl and alkynyl refer to unsaturated aliphatic groups analogous to alkyls, but which contain at least one double or triple carbon-carbon bond respectively. Suitable alkenyl and alkynyl groups include groups having 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms.
- aromatic group or "aryl group” includes unsaturated and aromatic cyclic hydrocarbons as well as unsaturated and aromatic heterocycles containing one or more rings.
- Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycycle (e.g., tetralin).
- An "arylene” group is a divalent analog of an aryl group.
- Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
- heterocyclic group includes closed ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is an element other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated. Additionally, heterocyclic groups (such as pyrrolyl, pyridyl, isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character, in which case they may be referred to as “heteroaryl” or “heteroaromatic” groups.
- heteroaryl and heterocyclic (including heteroaryl) groups may also be substituted at one or more constituent atoms.
- heteroaromatic and heteroalicyclic groups may have 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O, or S heteroatoms.
- heteroatom includes atoms of any element other than carbon or hydrogen, preferred examples of which include nitrogen, oxygen, sulfur, and phosphorus. Heterocyclic groups may be saturated or unsaturated or aromatic.
- heterocycles include, but are not limited to, acridinyl; azocinyl; benzimidazolyl; benzofuranyl; benzothiofuranyl; benzothiophenyl; benzoxazolyl; benzthiazolyl; benztriazolyl; benztetrazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolinyl; carbazolyl; 4aH-carbazolyl; carbolinyl; chromanyl; chromenyl; cinnolinyl; decahydroquinolinyl; 2H,6H-l,5,2-dithiazinyl; dihydrofuro[2,3-b]tetrahydrofuran; furanyl; furazanyl; imidazolidinyl; imidazolinyl; imidazolyl; lH-indazolyl; indolenyl; indoliny
- 1,2,4-thiadiazolyl 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; thianthrenyl; thiazolyl; thienyl; fhienothiazolyl; thienooxazolyl; thienoimidazolyl; thiophenyl; triazinyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,2,5-triazolyl; 1,3,4-triazolyl; and xanthenyl.
- Preferred heterocycles include, but are not limited to, pyridinyl; furanyl; thienyl; pyrrolyl; pyrazolyl; pyrrolidinyl; imidazolyl; indolyl; benzimidazolyl; lH-indazolyl; oxazolidinyl; benzotriazolyl; benzisoxazolyl; oxindolyl; benzoxazolinyl; and isatinoyl groups. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- a common hydrocarbon aryl group is a phenyl group having one ring.
- Two-ring hydrocarbon aryl groups include naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, and azulenyl groups, as well as the partially hydrogenated analogs thereof such as indanyl and tefrahydronaphthyl.
- Exemplary three- ring hydrocarbon aryl groups include acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl groups.
- Aryl groups also include heteromonocyclic aryl groups, i.e., single-ring heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups; and oxidized analogs thereof such as pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl, and thiazolonyl groups.
- heteromonocyclic aryl groups i.e., single-ring heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups
- oxidized analogs thereof such as pyridonyl,
- the corresponding hydrogenated (i.e., non-aromatic) heteromonocylic groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperidino, piperazinyl, and morpholino and morpholinyl groups.
- Aryl groups also include fused two-ring heteroaryls such as indolyl, isoindolyl, indolizinyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromenyl, isochromenyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, isoquinolonyl, quinolonyl, naphthyridinyl, and pteridinyl groups, as well as the partially hydrogenated analogs such as chromanyl, isochromanyl, indolinyl, isoindolinyl, and tetrahydroindolyl groups.
- heteroaryls such as indolyl, isoindolyl, indolizinyl, indazolyl,
- Aryl groups also include fused three-ring groups such as phenoxathiinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and dibenzofuranyl groups.
- each Ar group may be selected from the group consisting of substituted or unsubstituted phenyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl groups.
- Further examples include substituted or unsubstituted phenyl, 1 -naphthyl, 2-na ⁇ hthyl, biphenyl, 1 -pyrrolyl, 2- pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl,
- amine refers to an unsubstituted or substituted moiety of the formula -NR a R b , in which R a and R are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and R b , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring.
- amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated.
- alkylamino as used herein means an alkyl group having an amino group attached thereto.
- Suitable alkylamino groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
- amino includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
- dialkylamino includes groups wherein the nitrogen atom is bound to at least two alkyl groups.
- arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
- alkylarylamino refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
- alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group substituted with an alkylamino group.
- amide or "aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
- alkylthio refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
- alkylcarboxyl as used herein means an alkyl group having a carboxyl group attached thereto.
- alkoxy as used herein means an alkyl group having an oxygen atom attached thereto.
- Representative alkoxy groups include groups having 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like.
- Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
- the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
- halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc., as well as perhalogenated alkyloxy groups.
- acylamino includes moieties wherein an amino moiety is bonded to an acyl group.
- the acylamino group includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
- alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone.
- carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
- ether or “ethereal” includes compounds or moieties which contain an oxygen bonded to two carbon atoms.
- an ether or ethereal group includes "alkoxyalkyl” which refers to an alkyl, alkenyl, or alkynyl group substituted with an alkoxy group.
- a “sulfonate” group is a -SO 3 H or -SO 3 " X + group bonded to a carbon atom, where X + is a cationic counter ion group.
- a "sulfonic acid” compound has a -SO H or -SO 3 " X + group bonded to a carbon atom, where X+ is a cationic group.
- a “sulfate” as used herein is a -OSO 3 H or -OSO ⁇ X* group bonded to a carbon atom, and a "sulfuric acid” compound has a -SO H or -OSOs ' X* group bonded to a carbon atom, where X + is a cationic group.
- a suitable cationic group may be a hydrogen atom. In certain cases, the cationic group may actually be another group on the therapeutic compound that is positively charged at physiological pH, for example an amino group.
- a "counter ion" is required to maintain electroneutrality.
- anionic counter ions include halide, triflate, sulfate, nitrate, hydroxide, carbonate, bicarbonate, acetate, phosphate, oxalate, cyanide, alkylcarboxylate, N-hydroxysuccinimide , N-hydroxybenzotriazole, alkoxide, thioalkoxide, alkane sulfonyloxy, halogenated alkane sulfonyloxy, arylsulfonyloxy, bisulfate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, or lactobionate.
- acyl refers to a carbonyl group that is attached through its carbon atom to a hydrogen (i.e., a formyl), an aliphatic group (e.g., acetyl), an aromatic group (e.g., benzoyl), and the like.
- substituted acyl includes acyl groups where one or more of the hydrogen atoms on one or more carbon atoms are replaced by, for example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), i ino,
- the chemical moieties of the compounds of the invention may be "substituted or unsubstituted.”
- substituted means that the moiety has substituents placed on the moiety other than hydrogen (i.e., in most cases, replacing a hydrogen), which allow the molecule to perform its intended function.
- substituents include moieties selected from straight or branched alkyl (preferably C1-C5), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably C ⁇ -C 6 ), thioalkyl (preferably C ⁇ -C 6 ), alkenyl (preferably C -C 6 ), alkynyl (preferably C 2 -C 6 ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, and heteroaryl groups, as well as (CR'R") 0-3 NR'R" (e.g., -NH 2 —
- a substituent may be selected from straight or branched alkyl (preferably C1-C 5 ), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably C ⁇ -C 6 ), thioalkyl (preferably C ⁇ -C 6 ), alkenyl (preferably C 2 -C 6 ), alkynyl (preferably C 2 -C 6 ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R") 0 - 10 NR'R" (e.g., -NH
- substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
- substituted is meant to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
- the permissible substituents can be one or more.
- a "substituent" may be selected from the group consisting of, for example, halogeno, trifluoromethyl, nitro, cyano, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C ⁇ -C 6 alkylcarbonyloxy, arylcarbonyloxy, C ⁇ -C 6 alkoxycarbonyloxy, aryloxycarbonyloxy, C ⁇ -C 6 alkylcarbonyl, C ⁇ -C 6 alkoxycarbonyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkoxy,
- R is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C 2 -C 10 alkyl group;
- R 2 is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
- Y is SO 3 " X + , OSOf X + , or SSOf X + ;
- X + is hydrogen, a cationic group, or ester-forming group; and each of L 1 and L 2 is independently a substituted or unsubstituted C ⁇ -C 5 alkyl group or absent, or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that when Ri is alkyl, L 1 is absent.
- the invention pertains to compounds of Formula II:
- R 1 is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C 2 -C 10 alkyl group;
- R 2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked to R 1 to form a heterocycle;
- Y is SO 3 X + , OSO 3 ⁇ X + , or SSO 3 " X: + ;
- X + is hydrogen, a cationic group, or an ester forming moiety; m is O or 1; n is i, 2, 3, or 4;
- L is substituted or unsubstituted C1-C 3 alkyl group or absent, or a phannaceutically acceptable salt, ester, or prodrug thereof, provided that when R 1 is alkyl, L is absent.
- R 2 is hydrogen.
- R 1 is straight chain alkyl, for example, ethyl, n-pentyl, n-heptyl, or n-octyl.
- R 1 is t-butyl.
- R 1 is C 7 -C 10 bicycloalkyl or tricycloalkyl, such as, for example, tricyclo[3.3.1.0 3 ' 7 ]decyl (or adamantyl), bicyclo[2.1.2]heptyl, or indolyl.
- R 1 is tefrahydronaphthyl.
- L 2 is -(CH 2 ) 3 -.
- L 2 is - (CH 2 ) - or -(CH ) 5 -.
- L 2 is -(CH 2 ) 2 -.
- L 2 is substituted alkyl, e.g., -CH -(CHOH)-CH -.
- L 1 is CH 2 CH 2 or absent.
- R 1 is branched alkyl, e.g., t-butyl. In another embodiment, R 1 is adamanyl. In another embodiment, R 1 is cyclic alkyl, e.g., cyclopropyl, cyclohexyl, cycloheptyl, cyclo-octyl, etc. The cycloalkyl moieties may be substituted ftirther, e.g., with additional alkyl groups or other groups which allow the molecule to perform its intended function. In another embodiment, R 1 is alkyl substituted with a propargyl moiety (e.g., HC ⁇ €-). In another embodiment, R 1 is cyclohexyl substituted with one or more methyl or propargyl groups.
- R 1 is cyclopropyl or cyclohexyl.
- the cyclopropyl or cyclohexyl group is subsituted with an ether group or an alkyl group.
- the ether group is a benzyl ether group.
- R 1 is alkyl, it is substituted with groups such as phenyl, or hydroxy.
- the compound of the invention is selected from the group consisting of:
- the invention pertains to compounds of Formula
- A is nitrogen or oxygen
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
- x is O, 1, 2, 3, or 4;
- n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
- R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6
- m is O, 1, 2, 3, or 4;
- R A , R B , R c , R D , and R E are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; and pharmaceutically acceptable salts, prodrugs and esters thereof, provided that said compound is not 3-(4-phenyl-l, 2, 3, 6-tetrahydro-l -pyridyl)- 1- propanesulfonic acid.
- n 2, 3 or 4.
- R 11 is a salt-forming cation.
- salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium.
- R ⁇ is an ester- forming group.
- An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
- A is oxygen.
- R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a double bond.
- R A , R B , R c , R D , and R E are each hydrogen.
- R ⁇ , R B , R D , and R E are each hydrogen and R c is a halogen, such as fluorine, chlorine, iodine, or bromine.
- R 3 or R 5a is a moiety of Formula Ilia.
- R , R 5 , R , and R are each hydrogen.
- R 4a , R 5a , R 6a , and R 7a are each hydrogen.
- R 3a is hydroxyl, cyano, acyl, or hydroxyl.
- R 11 and A taken together are a natural or unnatural amino acid residue or a pharmaceutically acceptable salt or ester thereof. Examples of amino acid residues include esters and salts of phenylalanine and leucine.
- n 0, 1, or 3.
- Examples of compounds of Formula III include, but are not limited to:
- the invention pertains to compounds of Formula IV :
- A is nitrogen or oxygen
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; is 0, 1, 2, 3, or 4; n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10; R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R 4 and R 5 taken together, with the ring atoms they are attached to, form a double bond, or R and R taken together, with the ring atoms they are attached to, form a double bond; m is 0, 1, 2, 3, or 4;
- R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl, and pharmaceutically acceptable salts, prodrugs and esters thereof.
- R 11 is a salt-forming cation.
- salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammomum.
- R 11 is an ester-forming group.
- An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
- A is oxygen.
- m is 0 or 1.
- n is 2, 3, or
- R 4 , R 5 , R 6 and R 7 are each hydrogen.
- R 4a , R 5a , R 6a , and R 7a also may be hydrogen.
- Examples of R 8 , R 9 , R 10 , R 11 , and R 12 include hydrogen.
- R 8 , R 9 , R 11 , R 12 are each hydrogen, and R 10 is a halogen, (e.g., fluorine, chlorine, bromine, or iodine), nitro, or alkyl (e.g., methyl, ethyl, butyl).
- A-R 11 may be the residue of an amino acid, e.g., a phenylalanine residue.
- R 9 , R 10 , R 11 and R 12 are each hydrogen, and R 8 is not hydrogen, e.g., halogen, e.g., fluorine, bromine, chlorine, or iodine.
- halogen e.g., fluorine, bromine, chlorine, or iodine.
- the invention pertains to compounds of Formula V: R 15 O
- R is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when
- A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
- x is O, 1, 2, 3, or 4;
- n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
- aa is a natural or unnatural amino acid residue;
- m is O, 1, 2, or 3;
- R 14 is hydrogen or protecting group
- R 15 is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts, esters, and prodrugs thereof.
- R 11 is a salt-forming cation. Examples of salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammomum.
- R 11 is an ester-forming group. An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
- A is oxygen.
- n 2, 3 or 4.
- m is 0.
- A-R 11 is a residue of a natural amino acid, or a salt or ester thereof.
- amino acid residues include, but are not limited to, leucine or phenylalanine residues, and pharmaceutically acceptable salts and esters thereof. Examples of possible esters include methyl, ethyl, and t-butyl.
- m is 1.
- aa include natural and unnatural amino acid residues such as phenylalanine, glycine, and leucine.
- (aa) m is a residue of phe-phe; and pharmaceutically acceptable salts or an appropriate protecting group.
- R 15 is hydrogen or substituted alkyl, e.g., arylalkyl.
- unnatural amino acid refers to any derivative of a natural amino acid including D forms, and - and /3-amino acid derivatives. It is noted that certain amino acids, e.g., hydroxyproline, that are classified as a non-natural amino acid herein, maybe found in nature within a certain organism or a particular protein. Amino acids with many different protecting groups appropriate for immediate use in the solid phase synthesis of peptides are commercially available.
- non-natural amino acids and amino acid derivatives may be used according to the invention (common abbreviations in parentheses): /3-alanine ( ⁇ -ALA), 7-aminobutyric acid (GABA), 2-aminobutyric acid (2-Abu), c,/3-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-l -carboxylic acid (ACPC), aminoisobutyric acid (Aib), 2-amino- thiazoline-4-carboxylic acid, 5 -amino valeric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-amino
- Examples of compounds o are not limited to:
- the invention pertains, at least in part, to compounds of Formula VI:
- n is i, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- A is oxygen or nitrogen;
- R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 1 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
- Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
- x is O, 1, 2, 3, or 4;
- R 19 is hydrogen, alkyl or aryl;
- Y 1 is oxygen, sulfur, or nitrogen
- Y 2 is carbon, nitrogen, or oxygen
- R is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; ⁇
- R is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent if Y 2 is oxygen;
- R is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or
- R is hydrogen, hydroxyl, alkoxy or aryloxy if Y is nitrogen; or R is absent if Y is oxygen or sulfur; or R 22 and R 21 maybe linked to form a cyclic moiety if Y 1 is nitrogen;
- R 23 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl, or absent if Y 2 is nitrogen or oxygen; or pharmaceutically acceptable salts, esters, and prodrugs thereof.
- R u is a salt-forming cation.
- salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium.
- the salt is a sodium salt.
- A is oxygen.
- Y 1 is oxygen or sulfur, and R 22 is absent.
- Y 2 is oxygen and R 21 is absent.
- R 20 include benzyl, aryl (e.g., phenyl), alkyl, cycloalkyl (e.g., adamantyl), etc.
- Y 2 is nitrogen and R 21 is hydrogen.
- R 21 is benzyl.
- R 20 and R 21 are linked to form a pyridyl ring.
- Y 1 is sulfur.
- the invention pertains to both salt forms and acid/base forms of the compounds of the invention.
- the invention pertains not only to the particular salt forms of compounds shown herein as salts, but also the invention includes other » pharmaceutically acceptable salts, and the acid and/or base form of the compound.
- the invention also pertains to salt forms of compounds shown herein.
- the invention does not pertain to the compounds described in WO 00/64420 and W0 96/28187. In this embodiment, the invention does not pertain to methods of using the compounds described in WO 00/64420 and W0 96/28187 for the treatment of diseases or disorders described therein. In a further embodiment, the invention pertains to methods of using the compounds described in WO 00/64420 and W0 96/28187 for methods described in this application, which are not described in WO 00/64420 and W0 96/28187. Both of WO 00/64420 and W0 96/28187 are incorporated by reference herein in their entirety.
- subject includes living organisms in which amyloidosis can occur, or which are susceptible to amyloid diseases, e.g., Alzheimer's disease, Down's syndrome, CAA, dialysis-related ( ⁇ 2 M) amyloidosis, secondary (AA) amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, etc.
- amyloid diseases e.g., Alzheimer's disease, Down's syndrome, CAA, dialysis-related ( ⁇ 2 M) amyloidosis, secondary (AA) amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, etc.
- subjects include humans, chickens, ducks, peking ducks, geese, deer, monkeys, cows, rabbits, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
- compositions of the present invention to a subject to be treated can be carried out using known procedures, at dosages and for periods of time effective to modulate amyloid aggregation or amyloid-induced toxicity in the subject as further described herein.
- An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of amyloid already deposited at the clinical site in the subject, the age, sex, and weight of the subject, and the ability of the therapeutic compound to modulate amyloid aggregation in the subject.
- Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- the subject is in need of treatment by the methods of the invention, and is selected for treatment based on this need.
- a subject in need of treatment is art-recognized, and includes subjects that have been identified as having a disease or disorder related to amyloid-deposition or amyloidosis, has a symptom of such a disease or disorder, or is at risk of such a disease or disorder, and would be expected, based on diagnosis, e.g., medical diagnosis, to benefit from treatment (e.g., curing, healing, preventing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease or disorder, the symptom of the disease or disorder, or the risk of the disease or disorder).
- the subject is a human.
- the subject may be a human over 30 years old, human over 40 years old, a human over 50 years old, a human over 60 years old, a human over 70 years old, a human over 80 years old, a human over 85 years old, a human over 90 years old, or a human over 95 years old.
- the subject may be a female human, including a postmenopausal female human, who may be on hormone (estrogen) replacement therapy.
- the subject may also be a male human.
- the subject is under 40 years old.
- a subject may be a human at risk for Alzheimer's disease, e.g., being over the age of 40 or having a predisposition for Alzheimer's disease.
- Alzheimer's disease predisposing factors identified or proposed in the scientific literature include, among others, a genotype predisposing a subject to Alzheimer's disease; environmental factors predisposing a subject to Alzheimer's disease; past history of infection by viral and bacterial agents predisposing a subject to Alzheimer's disease; and vascular factors predisposing a subject to Alzheimer's disease.
- a subject may also have one or more risk factors for cardiovascular disease (e.g., atherosclerosis of the coronary arteries, angina pectoris, and myocardial infarction) or cerebrovascular disease (e.g., atherosclerosis of the intracranial or extracranial arteries, stroke, syncope, and transient ischemic attacks), such as hypercholesterolemia, hypertension, diabetes, cigarette smoking, familial or previous history of coronary artery disease, cerebrovascular disease, and cardiovascular disease.
- cardiovascular disease e.g., atherosclerosis of the coronary arteries, angina pectoris, and myocardial infarction
- cerebrovascular disease e.g., atherosclerosis of the intracranial or extracranial arteries, stroke, syncope, and transient ischemic attacks
- hypercholesterolemia typically is defined as a serum total cholesterol concentration of greater than about 5.2 mmol/L (about 200 mg/dL).
- genotypes are believed to predispose a subject to Alzheimer's disease. These include the genotypes such as presenilin- 1, presenilin-2, and amyloid precursor protein (APP) missense mutations associated with familial Alzheimer's disease, and ⁇ -2-macroglobulin and LRP-1 genotypes, which are thought to increase the risk of acquiring sporadic (late-onset) Alzheimer's disease. E.van Uden, et al, J. Neurosci. 22(21), 9298-304 (2002); JJ.Goto, et al, J. Mol. Neurosci. 19(1-2), 37-41 (2002).
- APP amyloid precursor protein
- Another genetic risk factor for the development of Alzheimer's disease are variants of ApoE, the gene that encodes apolipoprotein E (particularly the apoE4 genotype), a constituent of the low-density lipoprotein particle. WJ Strittmatter, et al, Annu. Rev. Neurosci. 19, 53-77 (1996).
- the molecular mechanisms by which the various ApoE alleles alter the likelihood of developing Alzheimer's disease are unknown, however the role of ApoE in cholesterol metabolism is consistent with the growing body of evidence linking cholesterol metabolism to Alzheimer's disease. For example, chronic use of cholesterol-lowering drugs such as statins has recently been associated with a lower incidence of Alzheimer's disease, and cholesterol-lowering drugs have been shown to reduce pathology in APP transgenic mice.
- Alzheimer's disease has been suggested to alter A ⁇ trafficking (in and out of the brain), and favor retention of A ⁇ in the brain. ApoE4 has also been suggested to favor APP processing toward A ⁇ formation.
- Environmental factors have been proposed as predisposing a subject to Alzheimer's disease, including exposure to aluminum, although the epidemiological evidence is ambiguous, hi addition, prior infection by certain viral or bacterial agents may predispose a subject to Alzheimer's disease, including the herpes simplex virus and chlamydia pneumoniae.
- other predisposing factors for Alzheimer's disease can include risk factors for cardiovascular or cerebrovascular disease, including cigarette smoking, hypertension and diabetes. "At risk for Alzheimer's disease” also encompasses any other predisposing factors not listed above or as yet identified and includes an increased risk for Alzheimer's disease caused by head injury, medications, diet, or lifestyle.
- the methods of the present invention can be used for one or more of the following: to prevent Alzheimer's disease, to treat Alzheimer's disease, or ameliorate symptoms of Alzheimer's disease, or to regulate production of or levels of amyloid ⁇ (A ⁇ ) peptides.
- the human carries one or more mutations in the genes that encode /3-amyloid precursor protein, presenilin- 1 or presenilin-2.
- the human carries the Apolipoprotein e4 gene.
- the human has a family history of Alzheimer's Disease or a dementia illness.
- the human has trisomy 21 (Down's Syndrome).
- the subject has a normal or low serum total blood cholesterol level.
- the serum total blood cholesterol level is less than about 200 mg/dL, or less than about 180, and it can range from about 150 to about 200 mg/dL. In another embodiment, the total LDL cholesterol level is less than about 100 mg/dL, or less than about 90 mg/dL and can range from about 30 to about 100 mg/dL.
- Methods of measuring serum total blood cholesterol and total LDL cholesterol are well known to those skilled in the art and for example include those disclosed in WO 99/38498 at p.11, incorporated by reference herein. Methods of determining levels of other sterols in serum are disclosed in H. Gylling, et al, "Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999).
- the subject has an elevated serum total blood cholesterol level.
- the serum total cholesterol level is at least about 200 mg/dL, or at least about 220 mg/dL and can range from about 200 to about 1000 mg/dL.
- the subject has an elevated total LDL cholesterol level.
- the total LDL cholesterol level is greater than about 100 mg/dL, or even greater than about 110 mg/dL and can range from about 100 to about 1000 mg/dL.
- the human is at least about 40 years of age. In another embodiment, the human is at least about 60 years of age. In another embodiment, the human is at least about 70 years of age. In another embodiment, the human is at least about 80 years of age. In another embodiment, the human is at least about 85 years of age. In one embodiment, the human is between about 60 and about 100 years of age.
- the subject is shown to be at risk by a diagnostic brain imaging technique, for example, one that measures brain activity, plaque deposition, or brain atrophy.
- the subject is shown to be at risk by a cognitive test such as Clinical Dementia Rating (“CDR”), Alzheimer's Disease Assessment Scale- Cognition (“ADAS-Cog”), or Mini-Mental State Examination (“MMSE”).
- CDR Clinical Dementia Rating
- ADAS-Cog Alzheimer's Disease Assessment Scale- Cognition
- MMSE Mini-Mental State Examination
- the subject may exhibit a below average score on a cognitive test, as compared to a historical control of similar age and educational background.
- the subject may also exhibit a reduction in score as compared to previous scores of the subject on the same or similar cognition tests.
- a subject is typically assessed and rated in each of six cognitive and behavioural categories: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
- the assessment may include historical information provided by the subject, or preferably, a corroborator who knows the subject well.
- the subject is assessed and rated in each of these areas and the overall rating, (0, 0.5, 1.0, 2.0 or 3.0) determined.
- a rating of 0 is considered normal.
- a rating of 1.0 is considered to correspond to mild dementia.
- a subject with a CDR of 0.5 is characterized by mild consistent forgetfulness, partial recollection of events and
- the subject is assessed with a rating on the CDR of above 0, of above about 0.5, of above about 1.0, of above about 1.5, of above about 2.0, of above about 2.5, or at about 3.0.
- MMSE Mini-Mental State Examination
- the subject scores below 30 at least once on the MMSE. In another embodiment, the subject scores below about 28, below about 26, below about 24, below about 22, below about 20, below about 18, below about 16, below about 14, below about 12, below about 10, below about 8, below about 6, below about 4, below about 2, or below about 1.
- ADAS-Cog Alzheimer's Disease Assessment Scale
- SAD AS Standardized Alzheimer's Disease Assessment Scale
- the ADAS-cog is designed to measure, with the use of questionnaires, the progression and the severity of cognitive decline as seen in AD on a 70- point scale.
- the ADAS-cog scale quantifies the number of wrong answers. Consequently, a high score on the scale indicates a more severe case of cognitive decline,
- a subject exhibits a score of greater than 0, greater than about 5, greater than about 10, greater than about 15, greater than about 20, greater than about 25, greater than about 30, greater than about 35, greater than about 40, greater than about 45, greater than about 50, greater than about 55, greater than about 60, greater than about 65, greater than about 68, or about 70.
- the subject exhibits no symptoms of Alzheimer's Disease. In another embodiment, the subject is a human who is at least 40 years of age and exhibits no symptoms of Alzheimer's Disease. In another embodiment, the subject is a human who is at least 40 years of age and exhibits one or more symptoms of Alzheimer's Disease.
- the subject has Mild Cognitive Impairment. In a further embodiment, the subject has a CDR rating of about 0.5. In another embodiment, the subject has early Alzheimer's disease. n another embodiment, the subject has cerebral amyloid angiopathy.
- the levels of amyloid ⁇ peptides in a subject's plasma or cerebrospinal fluid (CSF) can be reduced from levels prior to treatment from about 10 to about 100 percent, or even about 50 to about 100 percent.
- the subject can have an elevated level of amyloid A ⁇ 40 and A ⁇ 42 peptide in the blood and CSF prior to treatment, according to the present methods, of greater than about 10 pg/mL, or greater than about 20 pg/mL, or greater than about 35 pg/mL, or even greater than about 40 pg/mL.
- the elevated level of amyloid A ⁇ 2 peptide can range from about 30 pg/mL to about 200 pg/mL, or even to about 500 pg/mL.
- the measurable levels of amyloid ⁇ peptide in the CSF may decrease from elevated levels present before onset of the disease. This effect is attributed to increased deposition, i.e., trapping of A ⁇ peptide in the brain instead of normal clearance from the brain into the CSF.
- the subject can have an elevated level of amyloid A ⁇ 0 peptide in the blood and CSF prior to treatment, according to the present methods, of greater than about 5 pg A ⁇ 2 /mL or greater than about 50 pg A ⁇ 40 /mL, or greater than about 400 pg/mL.
- the elevated level of amyloid A ⁇ 40 peptide can range from about 200 pg/mL to about 800 pg/mL, to even about 1000 pg/mL.
- the subject can have an elevated level of amyloid A ⁇ 2 peptide in the CSF prior to treatment, according to the present methods, of greater than about 5 pg/mL, or greater than about 10 pg/mL, or greater than about 200 pg/mL, or greater than about 500 pg/mL.
- the level of amyloid ⁇ peptide can range from about 10 pg/mL to about 1,000 pg/mL, or even about 100 pg/mL to about 1,000 pg/mL.
- the subject can have an elevated level of amyloid A ⁇ 40 peptide in the CSF prior to freatment according to the present methods of greater than about 10 pg/mL, or greater than about 50 pg/mL, or even greater than about 100 pg/mL.
- the level of amyloid ⁇ peptide can range from about 10 pg/mL to about 1,000 pg/mL.
- the amount of amyloid ⁇ peptide in the brain, CSF, blood, or plasma of a subject can be evaluated by enzyme-linked immunosorbent assay ("ELISA") or quantitative immunoblotting test methods or by quantitative SELDI-TOF which are well known to those skilled in the art, such as is disclosed by Zhang, et al, J. Biol. Chem. 274, 8966-72 (1999) and Zhang, et al, Biochemistry 40, 5049-55 (2001). See also, A.K.Vehmas, et al, DNA Cell Biol. 20(11), 713-21 (2001), P.Lewczuk, et al, Rapid Cornmun. Mass Spectrom.
- EIA Europium immunoassay
- Alzheimer's disease or a dementia may be applied as a prophylaxis against Alzheimer's disease or dementia for subject with such a predisposition, as in a subject, e.g., with a genomic mutation in the APP gene, the ApoE gene, or a presenilin gene.
- the subject may have (or may be predisposed to developing or may be suspected of having) vascular dementia, or senile dementia, Mild Cognitive Impairment, or early Alzheimer's disease.
- the subject may have another amyloid-related disease such as cerebral amyloid angiopathy, or the subject may have amyloid deposits, especially amyloid- ⁇ amyloid deposits in the brain.
- the present invention pertains to methods of using the compounds and pharmaceutical compositions thereof in the treatment and prevention of amyloid-related diseases.
- the pharmaceutical compositions of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid (e.g., AL amyloid protein ( ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid /dV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, ⁇ 2 M, AA, or AH amyloid protein) fibril formation, aggregation or deposition.
- AL amyloid protein ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid /dV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l
- a ⁇ , LAPP, ⁇ 2 M, AA, or AH amyloid protein fibril formation, aggregation or deposition.
- compositions of the invention may act to ameliorate the course of an amyloid-related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid from the brain; enhancing degradation of A ⁇ in the brain; or favoring clearance of amyloid protein prior to its organization in fibrils.
- Modulation of amyloid deposition includes both inhibition, as defined above, and enhancement of amyloid deposition or fibril formation.
- modulating is intended, therefore, to encompass prevention or stopping of amyloid formation or accumulation, inhibition or slowing down of further amyloid formation or accumulation in a subject with ongoing amyloidosis, e.g., already having amyloid deposition, and reducing or reversing of amyloid formation or accumulation in a subject with ongoing amyloidosis; and enhancing amyloid deposition, e.g., increasing the rate or amount of amyloid deposition in vivo or in vitro.
- Amyloid-enhancing compounds may be useful in animal models of amyloidosis, for example, to make possible the development of amyloid deposits in animals in a shorter period of time or to increase amyloid deposits over a selected period of time.
- Amyloid-enhancing compounds may be useful in screening assays for compounds which inhibit amyloidosis in vivo, for example, in animal models, cellular assays and in vitro assays for amyloidosis. Such compounds may be used, for example, to provide faster or more sensitive assays for compounds. Modulation of amyloid deposition is determined relative to an untreated subject or relative to the treated subject prior to treatment.
- “Inhibition" of amyloid deposition includes preventing or stopping of amyloid formation, e.g., fibrillogenesis, clearance of amyloid, e.g., soluble A ⁇ from brain, inhibiting or slowing down of further amyloid deposition in a subject with amyloidosis, e.g., already having amyloid deposits, and reducing or reversing amyloid fibrillogenesis or deposits in a subject with ongoing amyloidosis.
- Inhibition of amyloid deposition is determined relative to an untreated subject, or relative to the treated subject prior to treatment, or, e.g., determined by clinically measurable improvement, e.g., or in the case of a subject with brain amyloidosis, e.g., an Alzheimer's or cerebral amyloid angiopathy subject, stabilization of cognitive function or prevention of a further decrease in cognitive function (i.e., preventing, slowing, or stopping disease progression), or improvement of parameters such as the concentration of A ⁇ or tau in the CSF.
- treatment includes the application or administration of a composition of the invention to a subject, or application or administration of a composition of the invention to a cell or tissue from a subject, who has an amyloid-related disease or condition, has a symptom of such a disease or condition, or is at risk of (or susceptible to) such a disease or condition, with the purpose of curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
- treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a subject's physical or mental well-being; or, in some situations, preventing the onset of dementia.
- the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, a psychiatric evaluation, or a cognition test such as CDR, MMSE, ADAS-Cog, or another test known in the art.
- the methods of the invention successfully treat a subject's dementia by slowing the rate of or lessening the extent of cognitive decline.
- the term “treating” includes maintaining a subject's CDR rating at its base line rating or at 0.
- the term treating includes decreasing a subject's CDR rating by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more.
- the term “treating” also includes reducing the rate of the increase of a subject's CDR rating as compared to historical controls.
- the term includes reducing the rate of increase of a subject's CDR rating by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, of the increase of the historical or untreated controls.
- the term "treating” also includes maintaining a subject's score on the MMSE. The term “treating" includes increasing a subject's MMSE score by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points.
- the term also includes reducing the rate of the decrease of a subject's MMSE score as compared to historical controls.
- the term includes reducing the rate of decrease of a subject's MMSE score by about 5% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less or about 100% or less, of the decrease of the historical or untreated controls.
- the term "treating" includes maintaining a subject's score on the ADAS-Cog.
- treating includes decreasing a subject's ADAS- Cog score by about 1 point or greater, by about 2 points or greater, by about 3 points or greater, by about 4 points or greater, by about 5 points or greater, by about 7.5 points or greater, by about 10 points or greater, by about 12.5 points or greater, by about 15 points or greater, by about 17.5 points or greater, by about 20 points or greater, or by about 25 points or greater.
- the term also includes reducing the rate of the increase of a subject's ADAS-Cog score as compared to historical controls, hi another embodiment, the term includes reducing the rate of increase of a subject's ADAS-Cog score by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more br about 100% of the increase of the historical or untreated controls.
- the term "treating” e.g., for AA or AL amyloidosis, includes an increase in serum creatinine, e.g., an increase of creatinine clearance of 10% or greater, 20% or greater, 50% or greater, 80% or greater, 90% or greater, 100% or greater, 150% or greater, 200% or greater.
- the term “treating” also may induce remission of nephrotic syndrome (NS). It may also include remission of chronic diarrhea and or a gain in body weight, e.g., by 10% or greater, 15% or greater, or 20% or greater.
- the pharmaceutical compositions of the invention contain a compound that prevents or inhibits amyloid fibril formation, either in the brain or other organ of interest (acting locally) or throughout the entire body (acting systemically).
- Pharmaceutical compositions of the invention may be effective in controlling amyloid deposition either following their entry into the brain (following penetration of the blood brain barrier) or from the periphery.
- a compound of a pharmaceutical composition may alter the equilibrium of amyloidogenic peptide between the brain and the plasma so as to favor the exit of amyloidogenic peptide from the brain.
- amyloid protein soluble
- amyloid fibril formation and deposition due to a reduction of the amyloid protein pool in a specific organ, e.g., liver, spleen, pancreas, kidney, joints, brain, etc.
- An increase in the exit of amyloidogenic peptide from the brain would result in a decrease in amyloidogenic peptide brain concentration and therefore favor a decrease in amyloidogenic peptide deposition.
- an agent may lower the levels of amyloid ⁇ peptides, e.g., both A ⁇ 40 and A ⁇ 42 in the CSF and the plasma, or the agent may lower the levels of amyloid ⁇ peptides, e.g., A ⁇ 40 and A ⁇ 42 in the CSF and increase it in the plasma.
- compounds that penetrate the brain could control deposition by acting directly on brain amyloidogenic peptide e.g., by maintaining it in a non-fibrillar form or favoring its clearance from the brain, by increasing its degradation in the brain, or protecting brain cells from the detrimental effect of amyloidogenic peptide.
- an agent can also cause a decrease of the concentration of the amyloid protein (i.e., in a specific organ so that the critical concentration needed to trigger amyloid fibril formation or deposition is not reached).
- the compounds described herein may inhibit or reduce an interaction between amyloid and a cell surface constituent, for example, a glycosaminoglycan or proteoglycan constituent of a basement membrane, whereby inhibiting or reducing this interaction produces the observed neuroprotective and cell- protective effects.
- the compound may also prevent an amyloid peptide from binding or adhering to a cell surface, a process which is known to cause cell damage or toxicity.
- the compound may block amyloid-induced cellular toxicity or microglial activation or amyloid-induced neurotoxicity, or inhibit amyloid induced inflammation.
- the compound may also reduce the rate or amount of amyloid aggregation, fibril formation, or deposition, or the compound lessens the degree of amyloid deposition.
- amyloid- ⁇ disease may be used for mild cognitive impairment; vascular dementia; early Alzheimer's disease; Alzheimer's disease, including sporadic (non-hereditary) Alzheimer's disease and familial (hereditary) Alzheimer's disease; age- related cognitive decline; cerebral amyloid angiopathy ("CAA”); hereditary cerebral hemorrhage; senile dementia; Down's syndrome; inclusion body myositis (“LBM”); or age-related macular degeneration (“ARMD”).
- amyloid- ⁇ is a peptide having 39-43 amino-acids
- amyloid- ⁇ is an amyloidogenic peptide produced from ⁇ APP.
- Mild cognitive impairment is a condition characterized by a state of mild but measurable impairment in thinking skills, which is not necessarily associated with the presence of dementia. MCI frequently, but not necessarily, precedes Alzheimer's disease. It is a diagnosis that has most often been associated with mild memory problems, but it can also be characterized by mild impairments in other thinking skills, such as language or planning skills. However, in general, an individual with MCI will have more significant memory lapses than would be expected for someone of their age or educational background. As the condition progresses, a physician may change the diagnosis to "Mild-to-Moderate Cognitive Impairment," as is well understood in this art.
- Cerebral amyloid angiopathy refers to the specific deposition of amyloid fibrils in the walls of leptomingeal and cortical arteries, arterioles and in capillaries and veins. It is commonly associated with Alzheimer's disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke or dementia (see Frangione, et al, Amyloid: J. Protein Folding Disord. 8, Suppl. 1, 36-42 (2001)).
- CAA can occur sporadically or be hereditary. Multiple mutation sites in either A ⁇ or the APP gene have been identified and are clinically associated with either dementia or cerebral hemorrhage.
- Exemplary CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with amyloidosis of Icelandic type
- HCHWA-I the Dutch variant of HCHWA (HCHWA-D; a mutation in A ⁇ ); the Flemish mutation of A ⁇ ; the Arctic mutation of A ⁇ ; the Italian mutation of A ⁇ ; the Iowa mutation of A ⁇ ; familial British dementia; and familial Danish dementia.
- Cerebral amyloid angiopathy is known to be associated with cerebral hemorrhage (or hemorrhagic stroke).
- the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which amyloid- ⁇ protein is abnormally deposited at non- neurological locations, such as treatment of LBM by delivery of the compounds to muscle fibers.
- a ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium in individuals with age-related macular degeneration (ARMD).
- ARMD is a cause of irreversible vision loss in older individuals. It is believed that A ⁇ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of ARMD (Johnson, et al, Proc. Natl. Acad. Sci. USA 99(18), 11830-5 (2002)). Therefore, the invention also relates to the treatment or prevention of age- related macular degeneration.
- the invention relates to a method for preventing or inhibiting amyloid deposition in a subject.
- a method for preventing or inhibiting amyloid deposition in a subject comprises administering to a subject a therapeutically effective amount of a compound capable of reducing the concentration of amyloid (e.g., AL amyloid protein ( ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid IN, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, ⁇ M, AA, AH amyloid protein, or other amyloids), such that amyloid accumulation or deposition is prevented or inhibited.
- AL amyloid protein ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid IN, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l
- the invention in another aspect, relates to a method for preventing, reducing, or inhibiting amyloid deposition in a subject.
- a method for preventing, reducing, or inhibiting amyloid deposition in a subject comprises administering to a subject a therapeutically effective amount of a compound capable of inhibiting amyloid (e.g., AL amyloid protein ( ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ IN, amyloid ⁇ NI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, 2 M, AA, AH amyloid protein, or other amyloids), such that amyloid deposition is prevented, reduced, or inhibited.
- AL amyloid protein ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ IN, amyloid ⁇ NI, amyloid ⁇ , amyloid ⁇ l
- the invention also relates to a method for modulating, e.g., minimizing, amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing the concentration of amyloid (e.g., AL amyloid protein ( ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ IV, amyloid ⁇ NI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, ⁇ M, AA, AH amyloid protein, or another amyloid), such that said amyloid- associated damage to cells is modulated.
- a compound capable of reducing the concentration of amyloid e.g., AL amyloid protein ( ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ IV, amyloid ⁇ NI, amyloid ⁇ , amyloid ⁇ l
- the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concentration of amyloid or reducing the interaction of an amyloid with a cell surface.
- the invention also includes a method for directly or indirectly preventing cell death in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound capable of preventing amyloid (e.g., AL amyloid protein ( ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ lN, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, ⁇ 2 M, AA, AH amyloid protein, or other amyloid) mediated events that lead, directly or indirectly, to cell death.
- AL amyloid protein ⁇ or K -chain related, e.g., amyloid ⁇ , amyloid K, amyloid ⁇ lN, amyloid ⁇ VI, amy
- the method is used to treat Alzheimer's disease (e.g. sporadic or familial AD).
- the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA") or hereditary cerebral hemorrhage.
- the compounds of the invention may be used prophylactically or therapeutically in the treatment of disorders in which amyloid-beta peptide is abnormally deposited at non-neurological locations, such as treatment of IBM by delivery of the compounds to muscle fibers, or treatment of macular degeneration by delivery of the compound(s) of the invention to the basal surface of the retinal pigmented epithelium.
- the present invention also provides a method for modulating amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing the concentration of A ⁇ , or capable of mimimizing the interaction of A ⁇ (soluble oligomeric or fibnllary) with the cell surface, such that said amyloid-associated damage to cells is modulated.
- the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concentration of A ⁇ or reducing the interaction of A ⁇ with a cell surface.
- a method for preventing cell death in a subject comprising administering to a subject a therapeutically effective amount of a compound capable of preventing A/3-mediated events that lead, directly or indirectly, to cell death.
- the present invention also provides a method for modulating amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing the concentration of LAPP, or capable of mimimizing the interaction of LAPP (soluble oligomeric or fibrillary) with the cell surface, such that said amyloid-associated damage to cells is modulated.
- the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concentration of LAPP or reducing the interaction of LAPP with a cell surface.
- a method for preventing cell death in a subject comprising administering to a subject a therapeutically effective amount of a compound capable of preventing IAPP-mediated events that lead, directly or indirectly, to cell death.
- This invention also provides methods and compositions which are useful in the treatment of amyloidosis.
- the methods of the invention involve administering to a subject a therapeutic compound which inhibits amyloid deposition.
- the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs.
- the methods of the invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to (hereditary) amyloidosis or identified as being at risk to develop amyloidosis, e.g., hereditary, or identified as being at risk to develop amyloidosis.
- the invention includes a method of inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane to inhibit amyloid deposition.
- the constituent of basement membrane is a glycoprotein or proteoglycan, preferably heparan sulfate proteoglycan.
- a therapeutic compound used in this method may interfere with binding of a basement membrane constituent to a target binding site on an amyloidogenic protein, thereby inhibiting amyloid deposition.
- the methods of the invention involve administering to a subject a therapeutic compound which inhibits amyloid deposition.
- “Inhibition of amyloid deposition” includes the prevention of amyloid formation, inhibition of further amyloid deposition in a subject with ongoing amyloidosis and reduction of amyloid deposits in a subject with ongoing amyloidosis. Inhibition of amyloid deposition is determined relative to an untreated subject or relative to the treated subject prior to treatment. In an embodiment, amyloid deposition is inhibited by inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane.
- Basis membrane refers to an extracellular matrix comprising glycoproteins and proteoglycans, including laminin, collagen type IN, fibronectin, perlecan, agrin, dermatan sulfate, and heparan sulfate proteoglycan (HSPG).
- amyloid deposition is inhibited by interfering with an interaction between an amyloidogenic protein and a sulfated glycosaminoglycan such as HSPG, dermatan sulfate, perlecan or agrin sulfate.
- Sulfated glycosaminoglycans are known to be present in all types of amyloids (see Snow, et al Lab. Invest.
- amyloid deposition and HSPG deposition occur coincidentally in animal models of amyloidosis (see Snow, et al. Lab. Invest. 56, 665-75 (1987) and Gervais, F. et al. Curr. Med. Chem., 3, 361-370 (2003)).
- Consensus binding site motifs for HSPG in amyloidogenic proteins have been described (see, e.g., Cardin and Weintraub Arteriosclerosis 9, 21-32 (1989)).
- the ability of a compound to prevent or block the formation or deposition of amyloid may reside in its ability to bind to non-fibrillar, soluble amyloid protein and to maintain its solubililty.
- an in vitro binding assay such as that described in US 5,164,295, the contents of which are hereby inco ⁇ orated by reference.
- the ability of a compound to bind to an amyloidogenic protein or to inhibit the binding of a basement membrane constituent (e.g. HSPG) to an amyloidogenic protein (e.g. A ⁇ ) can be measured using a mass spectrometry assay where soluble protein, e.g.A ⁇ , IAPP, ⁇ M is incubated with the compound.
- a ⁇ will induce a change in the mass spectrum of the protein.
- Exemplary protocols for a mass spectrometry assay employing A ⁇ and LAPP can be found in the Examples, the results of which are provided in Table 3.
- the protocol can readily be modified to adjust the sensitivity of the data, e.g., by adjusting the amount of protein and/or compound employed.
- binding might be detected for test compounds noted as not having detectable binding employing less sensitive test protocols.
- test compound (20 ⁇ M) is incubated with 50 ⁇ M A ⁇ (l-40) fibers for 1 hour at 37°C in Tris buffered saline (20 mM Tris, 150 mM NaCl, pH 7.4 containing 0.01 sodium azide). Following incubation, the solution is centrifuged for 20 minutes at 21,000 g to sediment the A ⁇ (l-40) fibers along with any bound test compound. The amount of test compound remaining in the supernatant can then be determined by reading the absorbance.
- test compound bound can then be calculated by comparing the amount remaining in the supernatants of incubations with A ⁇ to the amount remaining in control incubations which do not contain A ⁇ fibers.
- Thioflavin T and Congo Red both of which are known to bind to A ⁇ fibers, may be included in each assay run as positive controls.
- test compounds can be diluted to 40 ⁇ M, which would be twice the concentration in the final test, and then scanned using the Hewlett Packard 8453 UN/VIS spectrophotometer to determine if the absorbance is sufficient for detection.
- the invention in another embodiment, pertains to a method for improving cognition in a subject suffering from an amyloid-related disease.
- the method includes administering an effective amount of a therapeutic compound of the invention, such that the subject's cognition is improved.
- the subject's cognition can be tested using methods known in the art such as the Clinical Dementia Rating (“CDR”), Mini-Mental State Examination (“MMSE”), and the Alzheimer's Disease Assessment Scale- Cognition (“ADAS-Cog”).
- CDR Clinical Dementia Rating
- MMSE Mini-Mental State Examination
- ADAS-Cog Alzheimer's Disease Assessment Scale- Cognition
- the invention in another embodiment, pertains to a method for treating a subject for an amyloid-related disease.
- the method includes admimstering a cognitive test to a subject prior to administration of a compound of the invention, administering an effective amount of a compound of the invention to the subject, and administering a cognitive test to the subject subsequent to administration of the compound, such that the subject is treated for the amyloid-related disease, wherein the subject's score on said cognitive test is improved.
- a subject's CDR is maintained at 0.
- a subject's CDR is decreased (e.g., improved) by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more.
- the rate of increase of a subject's CDR rating is reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more of the increase of the historical or untreated controls.
- a subject's score on the MMSE is maintained.
- the subject's score on the MMSE may be increased by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points.
- the rate of the decrease of a subject's MMSE score as compared to historical controls is reduced.
- the rate of the decrease of a subject's MMSE score may be reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more of the decrease of the historical or untreated controls.
- the invention pertains to a method for treating, slowing or stopping an amyloid-related disease associated with cognitve impairment, by administering to a subject an effective amount of a therapeutic compound of the invention, wherein the annual deterioration of the subject's cognition as measured by ADAS-Cog is less than 8 points per year, less the 6 points per year, less than 5 points per year, less than 4 points per year, or less than 3 points per year.
- the invention pertains to a method for treating, slowing or stopping an amyloid-related disease associated with cognition by administering an effective amount of a therapeutic compound of the invention such that the subject's cognition as measured by ADAS-Cog remains constant over a year.
- Constant includes fluctuations of no more than 2 points. Remaining constant includes fluctuations of two points or less in either direction.
- the subject's cognition improves by 2 points or greater per year, 3 points or greater per year, 4 point or greater per year, 5 points or greater per year, 6 points or greater per year, 7 points or greater per year, 8 points or greater per year, etc. as measured by the ADAS-Cog.
- the rate of the increase of a subject's ADAS-Cog score as compared to historical controls is reduced.
- the rate of the increase of a subject's ADAS-Cog score may be reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70%) or more, about 80% or more, about 90%> or more or about 100% of the increase of the historical or untreated controls.
- the ratio of A ⁇ 42:A ⁇ 40 in the CSF or plasma of a subject decreases by about 15% or more, about 20%> or more, about 25% or more, about 30%) or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more.
- the levels of A ⁇ in the subject's cerebrospinal fluid decrease by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, about 75% or more, or about 90% or more.
- values and ranges are provided herein, e.g., in ages of subject populations, dosages, and blood levels, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values in these values and ranges may also be the upper or lower limits of a range.
- the invention pertains to any novel chemical compound described herein. That is, the invention relates to novel compounds, and novel methods of their use as described herein, which are within the scope of the Formulae disclosed herein, and which are not disclosed in the cited Patents and Patent Applications. Synthesis of Compounds of the Invention
- the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here. Functional and structural equivalents of the compounds described herein and which have the same general properties, wherein one or more simple variations of substituents are made which do not adversely affect the essential nature or the utility of the compound are also included.
- the compounds of the present invention may be readily prepared in accordance with the synthesis schemes and protocols described herein, as illustrated in the specific procedures provided. However, those skilled in the art will recognize that other synthetic pathways for forming the compounds of this invention may be used, and that the following is provided merely by way of example, and is not limiting to the present invention. See, e.g., "Comprehensive Organic Transformations” by R. Larock, NCH Publishers (1989). It will be further recognized that various protecting and deprotecting strategies will be employed that are standard in the art (See, e.g., "Protective Groups in Organic Synthesis” by Greene and Wuts). Those skilled in the relevant arts will recognize that the selection of any particular protecting group (e.g., amine and carboxyl protecting groups) will depend on the stability of the protected moiety with regards to the subsequent reaction conditions and will understand the appropriate selections.
- protecting group e.g., amine and carboxyl protecting groups
- Suitable solvents are liquids at ambient room temperature and pressure or remain in the liquid state under the temperature and pressure conditions used in the reaction.
- Useful solvents are not particularly restricted provided that they do not interfere with the reaction itself (that is, they preferably are inert solvents), and they dissolve a certain amount of the reactants. Depending on the circumstances, solvents may be distilled or degassed.
- Solvents may be, for example, aliphatic hydrocarbons (e.g., hexanes, heptanes, ligroin, petroleum ether, cyclohexane, or methylcyclohexane) and halogenated hydrocarbons (e.g., methylenechloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlororbenzene); aromatic hydrocarbons (e.g., benzene, toluene, tetrahydronaphthalene, ethylbenzene, or xylene); ethers (e.g., diglyme, methyl-tert-butyl ether, methyl-tert-amyl ether, ethyl-tert-butyl ether, diethylether, diisopropylether, tetrahydrofuran or methyltetrahydrofurans, dioxane,
- the product is isolated from the reaction mixture according to standard techniques. For example, the solvent is removed by evaporation or filtration if the product is solid, optionally under reduced pressure.
- water may be added to the residue to make the aqueous layer acidic or basic and the precipitated compound filtered, although care should be exercised when handling water-sensitive compounds.
- water may be added to the reaction mixture with a hydrophobic solvent to extract the target compound.
- the organic layer may be washed with water, dried over anhydrous magnesium sulphate or sodium sulphate, and the solvent is evaporated to obtain the target compound.
- the target compound thus obtained maybe purified, if necessary, e.g., by recrystallization, reprecipitation, chromatography, or by converting it to a salt by addition of an acid or base.
- the compounds of the invention may be supplied in a solution with an appropriate solvent or in a solvent-free form (e.g., lyophihzed).
- the compounds and buffers necessary for carrying out the methods of the invention may be packaged as a kit, optionlly including a container.
- the kit may be commercially used for treating or preventing amyloid-related disease according to the methods described herein and may include instructions for use in a method of the invention.
- Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
- the additional kit components are present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components optionally further comprise buffers.
- the term "container” includes any receptacle for holding the therapeutic compounds.
- the container is the packaging that contains the compound.
- the container is not the packaging that contains the compound, i.e., the container is a receptacle, such as a box or vial that contains the packaged compound or unpackaged compound and the instructions for use of the compound.
- packaging techniques are well known in the art. It should be understood that the instructions for use of the therapeutic compound may be contained on the packaging containing the therapeutic compound, and as such the instructions form an increased functional relationship to the packaged product.
- the present invention relates to pharmaceutical compositions comprising agents according to any of the Formulae herein for the treatment of an amyloid-related disease, as well as methods of manufacturing such pharmaceutical compositions.
- the agents of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, in the patents and patent applications refered to herein, or by modifications thereof, using readily available starting materials, reagents and cdnventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here. Functional and structural equivalents of the agents described herein and which have the same general properties, wherein one or more simple variations of substituents are made which do not adversely affect the essential nature or the utility of the agent are also included.
- the agents of the invention may be supplied in a solution with an appropriate solvent or in a solvent-free form (e.g., lyophihzed).
- the agents and buffers necessary for carrying out the methods of the invention may be packaged as a kit.
- the kit may be commercially used according to the methods described herein and may include instructions for use in a method of the invention.
- Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
- the additional kit components are present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components optionally further comprise buffers.
- the therapeutic agent may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally.
- Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
- the agent may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
- suitable diluents include saline and aqueous buffer solutions.
- Liposomes include water-in-oil-in- water CGF emulsions as well as conventional liposomes (Strejan et al, J. Neuroimmunol 7, 27 (1984)).
- compositions suitable for mjectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile mjectable solutions or dispersion.
- the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- Suitable pharmaceutically acceptable vehicles include, without limitation, any non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal, mucosal, transdermal, intravascular (IN), intraarterial (LA), intramuscular (LM), and subcutaneous (SC) administration routes, such as phosphate buffer saline (PBS).
- any non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal, mucosal, transdermal, intravascular (IN), intraarterial (LA), intramuscular (LM), and subcutaneous (SC) administration routes such as phosphate buffer saline (PBS).
- PBS phosphate buffer saline
- the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, tbimerosal, and the like.
- isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
- Sterile injectable solutions can be prepared by incorporating the therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the therapeutic agent can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- the therapeutic agent and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
- the therapeutic agent may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- the percentage of the therapeutic agent in the compositions and preparations may, of course, be varied.
- the amount of the therapeutic agent in such therapeutically useful compositions is such that a suitable dosage will be obtained.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
- the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic agent and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic agent for the treatment of amyloid deposition in subjects.
- the present invention therefore includes phannaceutical formulations comprising the agents of the Formulae described herein, including pharmaceutically acceptable salts thereof, in pharmaceutically acceptable vehicles for aerosol, oral and parenteral administration. Also, the present invention includes such agents, or salts thereof, which have been lyophihzed and which may be reconstituted to form pharmaceutically acceptable formulations for administration, as by intravenous, intramuscular, or subcutaneous injection. Administration may also be intradermal or transdermal.
- an agent of the Formulae described herein, and pharmaceutically acceptable salts thereof may be administered orally or through inhalation as a solid, or may be administered intramuscularly or intra ⁇ enously as a solution, suspension or emulsion.
- the agents or salts may also be administered by inhalation, intravenously or intramuscularly as a liposomal suspension.
- Pharmaceutical formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of the desired agent of any Formula herein, or a salt thereof, or a plurality of solid particles of the agent or salt. The desired formulation may be placed in a small chamber and nebulized.
- Nebuhzation may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the agents or salts.
- the liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns.
- the solid particles can be obtained by processing the solid agent of any Formula described herein, or a salt thereof, in any appropriate manner known in the art, such as by micronization.
- the size of the solid particles or droplets will be, for example, from about 1 to about 2 microns. Ln this respect, commercial nebulizers are available to achieve this purpose.
- a pharmaceutical formulation suitable for administration as an aerosol may be in the form of a liquid, the formulation will comprise a water-soluble agent of any Formula described herein, or a salt thereof, in a carrier which comprises water.
- a surfactant may be present which lowers the surface tension of the formulation sufficiently to result in the formation of droplets within the desired size range when subjected to nebuhzation.
- Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
- the pharmaceutically acceptable vehicles suitable for preparation of such compositions are well known in the art.
- Typical components of carriers for syrups, ehxirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
- typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth, and sodium alginate;
- typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
- Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
- compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject agent is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
- dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, and shellac.
- compositions useful for attaining systemic delivery of the subject agents include sublingual, buccal and nasal dosage forms.
- Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
- compositions of this invention can also be administered topically to a subject, e.g. , by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch".
- Such compositions include, for example, lotions, creams, solutions, gels and solids.
- These topical compositions may comprise an effective amount, usually at least about 0.1%, or even from about 1% to about 5%, of an agent of the invention.
- Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
- the carrier is organic in nature and capable of having dispersed or dissolved therein the therapeutic agent.
- the carrier may include pharmaceutically acceptable emolients, emulsifiers, thickening agents, solvents and the like.
- active agents are administered at a therapeutically effective dosage sufficient to inhibit amyloid deposition in a' subject.
- a "therapeutically effective" dosage inhibits amyloid deposition by, for example, at least about 20%>, or by at least about 40%o, or even by at least about 60%>, or by at least about 80%> relative to untreated subjects.
- a "therapeutically effective" dosage stabilizes cognitive function or prevents a further decrease in cognitive function (i.e., preventing, slowing, or stopping disease progression).
- the present invention accordingly provides therapeutic drugs.
- terapéutica an agent having a beneficial ameliorative or prophylactic effect on a specific disease or condition in a living human or non-human animal.
- the agent may improve or stabilize specific organ function.
- renal function may be stabilized or improved by 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or by greater than 90% ⁇ .
- the agent may maintain or increase ⁇ -islet cell function, as determined by insulin concentration or the Pro-LAPP/IAPP ratio.
- the Pro-IAPP/IAPP ratio is increased by about 10% or greater, about 20% or greater, about 30% or greater, about 40%> or greater, or by about 50%>.
- the ratio is increased up to 50%.
- a therapeutically effective amount of the agent may be effective to improve glycemia or insulin levels.
- the active agents are administered at a therapeutically effective dosage sufficient to treat AA (secondary) amyloidosis and/or AL (primary) amyloidosis, by stabilizing renal function, decreasing proteinuria, increasing creatinine clearance (e.g., by at least 50% or greater or by at least 100% or greater), remission of chronic diarrhea, or by weight gain (e.g., 10% or greater).
- the agents may be administered at a therapeutically effective dosage sufficient to improve nephrotic syndrome.
- active agents may be administered at a therapeutically effective dosage sufficient to decrease deposition in a subject of amyloid protein, e.g., A/340 or A/342.
- a therapeutically effective dosage decreases amyloid deposition by, for example, at least about 15%, or by at least about 40%, or even by at least 60%, or at least by about 80% relative to untreated subjects.
- active agents are administered at a therapeutically effective dosage sufficient to increase or enhance amyloid protein, e.g., A/340 or A/342, in the blood, CSF, or plasma of a subject.
- a therapeutically effective dosage increases the concentration by, for example, at least about 15%, or by at least about 40%, or even by at least 60%, or at least by about 80% relative to untreated subjects.
- active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's CDR rating at its base line rating or at 0.
- the active agents are administered at a therapeutically effective dosage sufficient to decrease a subject's CDR rating by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more.
- the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate of the increase of a subject's CDR rating as compared to historical or untreated controls, hi another embodiment, the therapeutically effective ,dosage s sufficient to reduce the rate of increase of a subject's CDR rating (relative to untreated subjects) by about 5% or greater, about 10% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater or about 100% or greater.
- active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's score on the MMSE.
- the active agents are administered at a therapeutically effective dosage sufficient to increase a subject's MMSE score by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points, hi another embodiment, the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate of the decrease of a subject's MMSE score as compared to historical controls.
- the therapeutically effective dosage is sufficient to reduce the rate of decrease of a subject's MMSE score may be about 5% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, about 50% or less, about 60%. or less, about 70% or less, about 80% or less, about 90%. or less or about 100%> or less, of the decrease of the historical or untreated controls.
- active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's score on the ADAS-Cog.
- the active agents are administered at a therapeutically effective dosage sufficient to decrease a subject's ADAS-Cog score by about 2 points or greater, by about 3 points or greater, by about 4 points or greater, by about 5 points or greater, by about 7.5 points or greater, by about 10 points or greater, by about 12.5 points or greater, by about 15 points or greater, by about 17.5 points or greater, by about 20 points or greater, or by about 25 points or greater.
- the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate of the increase of a subject's ADAS-Cog scores as compared to historical or untreated controls.
- the therapeutically effective dosage is sufficient to reduce the rate of increase of a subject's ADAS-Cog scores (relative to untreated subjects) by about 5% or greater, about 10% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater or about 100% or greater.
- active agents are administered at a therapeutically effective dosage sufficient to decrease the ratio of A ⁇ 42:A ⁇ 40 in the CSF or plasma of a subject by about 15% or more, about 20% or more, about 25% or more, about 30%> or more, about 35%) or more, about 40% or more, about 45% or more, or about 50% or more.
- active agents are administered at a therapeutically effective dosage sufficient to lower levels of A ⁇ in the CSF or plasma of a subject by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, about 75%) or more, or about 95%> or more.
- Toxicity and therapeutic efficacy of such agents can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50%> of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50, and usually a larger therapeutic index is more efficacious. While agents that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to unaffected cells and, thereby, reduce side effects.
- doses depend upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher.
- the dose(s) of the small molecule will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the small molecule to have upon the subject.
- Exemplary doses include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
- appropriate doses depend upon the potency. Such appropriate doses may be determined using the assays described herein. When one or, more of these compounds is to be administered to an animal (e.g. , a human), a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
- the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
- an agent to inhibit amyloid deposition can be evaluated in an animal model system that may be predictive of efficacy in inhibiting amyloid deposition in human diseases, such as a transgenic mouse expressing human APP or other relevant animal models where A ⁇ deposition is seen or for example in an animal model of AA amyloidosis.
- the ability of an agent to prevent or reduce cognitive impairment in a model system may be indicative of efficacy in humans.
- the ability of an agent can be evaluated by examining the ability of the agent to inhibit amyloid fibril formation in vitro, e.g., using a fibrillogenesis assay such as that described herein, including a ThT, CD, or EM assay.
- the binding of an agent to amyloid fibrils may be measured using a MS assay as described herein.
- the ability of the agent to protect cells from amyloid induced toxicity is determined in vitro using biochemical assays to determine percent cell death induced by amyloid protein.
- the ability of an agent to modulate renal function may also be evaluated in an appropriate animal model system.
- the therapeutic agent of the invention may be also be administered ex vivo to inhibit amyloid deposition or treat certain amyloid-related diseases, such as ⁇ M amyloidosis and other amyloidoses related to dialysis.
- Ex vivo administration of the therapeutic agents of the invention can be accomplished by contacting a body fluid (e.g., blood, plasma, etc.) with a therapeutic compound of the invention such that the therapeutic compound is capable of performing its intended function and administering the body fluid to the subject.
- the therapeutic compound of the invention may perform its function ex vivo (e.g., dialysis filter), in vivo (e.g., administered with the body fluid), or both.
- a therapeutic compound of the invention may be used to reduce plasma ⁇ 2 M levels and/or maintain ⁇ 2 M in its soluble form ex vivo, in vivo, or both.
- the compound prevents or treats amyloid-related diseases, such as for example Alzheimer's disease, CAA, diabetes related amyloidosis, AL amyloidosis, Down's syndrome, or /3 2 M amyloidosis.
- amyloid-related diseases such as for example Alzheimer's disease, CAA, diabetes related amyloidosis, AL amyloidosis, Down's syndrome, or /3 2 M amyloidosis.
- the compound may reverse or favor deposition of amyloid or the compound may favor plaque clearance or slow deposition.
- the compound may decrease the amyloid concentration in the brain of a subject versus an untreated subject.
- the compound may penetrate into the brain by crossing the blood-brain barrier ("BBB”) to exert its biological effect.
- BBB blood-brain barrier
- the compound may maintain soluble amyloid in a non-fibrillar form, or alternatively, the compound may increase the rate of clearance of soluble amyloid from the brain of a subject versus an untreated subject.
- the compound may also increase the rate of degradation of A ⁇ in the brain prior to organization into fibrils.
- a compound may also act in the periphery, causing a change in the equilibrium of the amyloid protein concentration in the two compartments (i.e., systemic vs. central), in which case a compound may not be required to penetrate the brain to decrease the concentration of A ⁇ in the brain (a "sink" effect).
- Agents of the invention that exert their physiological effect in vivo in the brain may be more useful if they gain access to target cells in the brain.
- Non-limiting examples of brain cells are neurons, glial cells (astrocytes, oligodendrocytes, microglia), cerebrovascular cells (muscle cells, endothelial cells), and cells that comprise the meninges.
- the blood brain barrier typically restricts access to brain cells by acting as a physical and functional blockade that separates the brain parenchyma from the systemic circulation (see, e.g., Pardridge, et al, J. Neurovirol 5(6), 556-69 (1999); Rubin, et al, Rev. Neurosci. 22, 11-28 (1999)).
- Circulating molecules are normally able to gain access to brain cells via one of two processes: lipid-mediated transport through the BBB by free diffusion, or active (or catalyzed) transport.
- the agents of the invention may be formulated to improve distribution in vivo, for example as powdered or liquid tablet or solution for oral administration or as a nasal spray, nose drops, a gel or ointment, through a tube or catheter, by syringe, by packtail, by pledget, or by submucosal infusion.
- the blood-brain barrier excludes many highly hydrophilic agents. To ensure that the more hydrophilic therapeutic agents of the invention cross the BBB, they may be formulated, for example, in liposomes.
- the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties” or “targeting groups” or “transporting vectors"), thus providing targeted drug delivery (see, e.g., VN. RanadeJ Clin. Pharmacol. 29, 685 (1989)).
- the agents maybe linked to targeting groups that facilitate penetration of the blood brain barrier.
- the method of the present invention employs a naturally occurring polyamine linked to an agent that is a small molecule and is useful for inhibiting e.g., A ⁇ deposition.
- BBB transport vectors include cationized albumin or the OX26 monoclonal antibody to the transferrin receptor; these proteins undergo abso ⁇ tive-mediated and receptor-mediated transcytosis through the BBB, respectively.
- Natural cell metabolites that may be used as targeting groups include, mter alia, putirescine, spermidine, spermine, or DHA.
- Other exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No.
- BBB transport vectors examples include factors such as insulin, insulin-like growth factors (“IGF-I,” and “IGF-II”), angiotensin II, atrial and brain natriuretic peptide (“ANP,” and “BNP”), interleukin I (“IL-1”) and transferrin. Monoclonal antibodies to the receptors that bind these factors may also be used as BBB transport vectors.
- BBB transport vectors targeting mechanisms for abso ⁇ tive-mediated transcytosis include cationic moieties such as cationized LDL, albumin or horseradish peroxidase coupled with polylysine, cationized albumin or cationized immunoglobulins.
- Small basic oligopeptides such as the dyno ⁇ hin analogue E-2078 and the ACTH analogue ebiratide may also cross the brain via abso ⁇ tive-mediated transcytosis and are potential transport vectors.
- Other BBB transport vectors target systems for transporting nutrients into the brain.
- BBB transport vectors examples include hexose moieties, e.g., glucose and monocarboxylic acids, e.g., lactic acid and neutral amino acids, e.g., phenylalanine and amines, e.g., choline and basic amino acids, e.g., arginine, nucleosides, e.g., adenosine and purine bases, e.g., adenine, and thyroid hormone, e.g., triiodothyridine.
- Antibodies to the extracellular domain of nutrient transporters may also be used as transport vectors.
- Other possible vectors include angiotensin II and ANP, which may be involved in regulating BBB permeability.
- the bond linking the therapeutic agent to the transport vector may be cleaved following transport into the brain in order to liberate the biologically active agent.
- exemplary linkers include disulfide bonds, ester-based linkages, thioether linkages, amide bonds, acid-labile linkages, and Schiff base linkages.
- Avidin biotin linkers in which avidin is covalently coupled to the BBB drug transport vector, may also be used. Avidin itself may be a drug transport vector.
- Transcytosis including receptor-mediated transport of compositions across the blood brain barrier, may also be suitable for the agents of the invention. Transferrin receptor-mediated delivery is disclosed in U.S. Pat. Nos.
- Transferrin-mediated transport is also known. P.M. Friden, et al, Pharmacol. Exp. Ther. 278, 1491-98 (1996); H.J. Lee, J. Pharmacol Exp. Ther. 292, 1048-52 (2000). EGF receptor-mediated delivery is disclosed in
- 5,023,252 discloses the use of pharmaceutical compositions comprising a neurologically active drug and a compound for facilitating transport of the drug across the blood-brain barrier including a macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioester, dithioester, thioamide, ketone or lactone.
- U.S. Pat. No. 5,024,998 discloses parenteral solutions of aqueous-insoluble drugs with cyclodextrin derivatives.
- U.S. Pat. No. 5,039,794 discloses the use of a metastatic tumor-derived egress factor for facilitating the transport of compounds across the blood-brain barrier.
- U.S. Pat. No. 5,124,146 discloses a method for delivery of therapeutic agents across the blood-brain barrier at sites of increase permeability associated with brain lesions.
- U.S. Pat. No. 5,153,179 discloses acylated glycerol and derivatives for use in a medicament for improved penetration of cell membranes.
- U.S. Pat. No. 5,177,064 discloses the use of lipoidal phosphonate derivatives of nucleoside antiviral agents for delivery across the blood-brain barrier.
- 5,254,342 discloses receptor- mediated transcytosis of the blood-brain barrier using the transferrin receptor in combination with pharmaceutical compounds that enhance or accelerate this process.
- U.S. Pat. No. 5,258,402 discloses treatment of epilepsy with imidate derivatives of anticonvulsive sulfamate.
- U.S. Pat. No. 5,270,312 discloses substituted piperazines as central nervous system agents.
- U.S. Pat. No. 5,284,876 discloses fatty acid conjugates of dopamine drugs.
- U.S. Pat. No. 5,389,623 discloses the use of lipid dihydropyridine derivatives of anti-inflammatory steroids or steroid sex hormones for delivery across the blood-brain barrier.
- U.S. Pat. No. 5,413,996 discloses acyloxyalkyl phosphonate conjugates of neurologically-active drugs for anionic sequestration of such drugs in brain tissue.
- U.S. Pat. No. 5,434,137 discloses methods for the selective opening of abnormal brain tissue capillaries using bradykinin infused into the carotid artery.
- U.S. Pat. No. 5,442,043 discloses a peptide conjugate between a peptide having a biological activity and incapable of crossing the blood-brain barrier and a peptide which exhibits no biological activity and is capable of passing the blood-brain barrier by receptor- mediated endocytosis.
- U.S. Pat. No. 5,466,683 discloses water soluble analogues of an anticonvulsant for the treatment of epilepsy.
- U.S. Pat. No. 5,525,727 discloses compositions for differential uptake and retention in brain tissue comprising a conjugate of a narcotic analgesic and agonists and antagonists thereof with a lipid form of dihydropyridine that forms a redox salt upon uptake across the blood-brain barrier that prevents partitioning back to the systemic circulation.
- Nitric oxide is a vasodilator of the peripheral vasculature in normal tissue of the body. Increasing generation of nitric oxide by nitric oxide synthase causes vasodilation without loss of blood pressure. The blood-pressure-independent increase in blood flow through brain tissue increases cerebral bioavailability of blood-born compositions. This increase in nitric oxide may be stimulated by administering L-arginine. As nitric oxide is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue.
- L-arginine may be used in the pharmaceutical compositions of the invention to enhance delivery of agents to brain tissue after introducing a pharmaceutical composition into the blood stream of the subject substantially contemporaneously with a blood flow enhancing amount of L-arginine, as described in WO 00/56328. Still further examples of modifications that enhance penetration of the blood brain barrier are described in International (PCT) Application Publication Number WO 85/02342, which discloses a drug composition comprising a glycerolipid or derivative thereof.
- PCT Publication Number WO 089/11299 discloses a chemical conjugate of an antibody with an enzyme which is delivered specifically to a brain lesion site for activating a separately-administered neurologically-active prodrug.
- WO 91/04014 discloses methods for delivering therapeutic and diagnostic agents across the blood-brain barrier by encapsulating the drugs in liposomes targeted to brain tissue using transport-specific receptor ligands or antibodies.
- PCT Publication Number WO 91/04745 discloses transport across the blood-brain barrier using cell adhesion molecules and fragments thereof to increase the permeability of tight junctions in vascular endothelium.
- PCT Publication Number WO 91/14438 discloses the use of a modified, chimeric monoclonal antibody for facilitating transport of substances across the blood-brain barrier.
- PCT Publication Number WO 94/01131 discloses lipidized proteins, including antibodies.
- PCT Publication Number WO 94/03424 discloses the use of amino acid derivatives as drug conjugates for facilitating transport across the blood-brain barrier.
- PCT Publication Number WO 94/06450 discloses conjugates of neurologically-active drugs with a dihydropyridine-type redox targeting moiety and comprising an amino acid linkage and an aliphatic residue.
- PCT Publication Number WO 94/02178 discloses antibody- targeted liposomes for delivery across the blood-brain barrier.
- PCT Publication Number WO 95/07092 discloses the use of drug- growth factor conjugates for delivering drugs across the blood-brain barrier.
- PCT Publication Number WO 96/00537 discloses polymeric microspheres as injectable drug- delivery vehicles for delivering bioactive agents to sites within the central nervous system.
- PCT Publication Number WO 96/04001 discloses omega-3-fatty acid conjugates of neurologically-active drugs for brain tissue delivery.
- PCT WO 96/22303 discloses fatty acid and glycerolipid conjugates of neurologically-active drugs for brain tissue delivery.
- an ester, amide or hydrazide derivative of an agent of the invention for example, from the corresponding carboxylic acid and a suitable reagent.
- a carboxylic acid- containing compound, or a reactive equivalent thereof may be reacted with a hydroxyl- containing compound, or a reactive equivalent thereof, so as to provide the corresponding ester.
- a carboxylic acid- containing compound, or a reactive equivalent thereof may be reacted with a hydroxyl- containing compound, or a reactive equivalent thereof, so as to provide the corresponding ester.
- the present invention is also related to prodrugs of the agents of the Formulae disclosed herein.
- Prodrugs are agents which are converted in vivo to active forms (see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8).
- Prodrugs can be used to alter the biodistribution (e.g., to allow agents which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular agent.
- a carboxylic acid group can be esterified, e.g., with a methyl group or an ethyl group to yield an ester.
- the ester When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
- An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate agent which subsequently decomposes to yield the active agent.
- the prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge, et al, "Pharmaceutical Salts", J. Pharm. Sci.
- the prodrugs can be prepared in situ during the final isolation and purification of the agents, or by separately reacting the purified agent in its free acid form with a suitable derivatizing agent.
- Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
- cleavable carboxylic acid prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., ethyl esters, propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexyl esters, cyclohexyl esters), lower alkenyl esters, dilower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower
- Certain embodiments of the present agents can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
- pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of agents of the present invention. These salts can be prepared in situ during the final isolation and purification of the agents of the invention, or by separately reacting a purified agent of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
- Representative salts include the hydrohalide (including hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethanesulfonate, and laurylsulphonate salts and the like. See, e.g., Berge et al, "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977).
- the agents of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with phannaceutically acceptable bases.
- pharmaceutically acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of agents of the present invention.
- salts can likewise be prepared in situ during the final isolation and purification of the agents, or by separately reacting the purified agent in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
- a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
- Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
- Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
- “Pharmaceutically acceptable salts” also includes, for example, derivatives of agents modified by making acid or base salts thereof, as described further below and elsewhere in the present application.
- Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
- Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammomum salts of the parent agent formed, for example, from non-toxic inorganic or organic acids.
- Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid
- organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tart
- salts may be synthesized from the parent agent which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
- test compounds were synthesized and screened by mass spectrometry ("MS") assays, except for selected compounds which were purchased from a commercial source.
- MS assay gives data on the ability of compounds to bind to proteins, in this example, to ⁇ -amyloid and LAPP. Ln the MS assay for A ⁇ 40, samples were prepared as aqueous solutions (adding
- the MS assay gives data on the ability of compounds to bind to soluble A ⁇ , whereas the ThT, EM and CD assays give data on inhibition of fibrillogenesis.
- the results from the assay for binding to A ⁇ are summarized in Table 3. Table 3, when a box is blank, it means a value for that compound for that assay
- the assay for LAPP was conducted under the same conditions except that 200 ⁇ M of test compound and 20 ⁇ M of solubilized LAPP were employed.
- the key below describes the codes used in Table 3 to quantify the binding based on the intensity of the abso ⁇ tion.
- Transgenic mice TgCRND8, expressing the human amyloid precursor protein (hAPP) develop a pathology resembling Alzheimer's disease.
- hAPP human amyloid precursor protein
- high levels of A ⁇ 40 and A ⁇ 42 have been documented in the plasma and the brain of these animals at 8-9 weeks of age, followed by early accumulation of amyloid plaques similar to the senile plaques observed in AD patients.
- These animals also display progressive cognitive deficits that parallel the appearance of degenerative changes. See, e.g., (Chishti, et al, J. Biol. Chem. 276, 21562-70 (2001).
- mice from the 3 rd and 4 th B6C3F1 generations were used in this example and given daily subcutaneous or oral administrations of one of a series of compounds for 14 or 28 days.
- the following abbreviations are used to designate these animals from the 3 rd and 4th generation backcross in the present protocol: TgCRND8-2.B6C3Fl(N 3 ); TgCRND8-2.B6C3Fl(N 4 ).
- Baseline animals (Group 1) consisted of naive TgCRND8-2. B6C3F1(N 3 ) at 11
- mice were used to determine the A/3 levels in the plasma and brain of naive transgenic animals at the initiation of treatment.
- animals received daily administration of their respective treatment for a period of 14 or 28 days (groups 2-21), at a dose of 250 mg/kg at 10 ml/kg or of vehicle only (water; group 2) or 1% methyl cellulose only
- mice used in this study were derived from a breeding colony at histitut Armand Frappier, and were well-acclimated to the animal facility environment prior to initiation of the study. Animals were assigned, according to age and gender, into the following experimental groups:
- Brains were weighted frozen and homogenized with 4 volumes of ice cold 50 mM Tris-Cl pH 8.0 buffer with protease inhibitor cocktail (4mL of buffer for lg of wet brain). Samples were spun at 15000g for 20 minutes and the supernatants were transfened to fresh tubes. One hundred fifty (150) ⁇ l from each supernatant were mixed with 250 ⁇ l of 8M guanidine-HCL/50mM Tris-HCL pH 8.0 (ratio of 0.6 vol supernatant: 1 vol 8M guanidium/Tris-HCL 50mM ⁇ H8.0) and 400 ⁇ L 5 M guanidium/Tris-HCL 50mM pH8.0 were added.
- the tubes were vortexed for 30 seconds and frozen at -80°C.
- pellets were treated with 7 volumes of 5 M guanidine- HCL/50mM Tris-HCL pH 8.0 (7mL of guanidine for lg of wet brain), vortexed for 30 seconds and frozen at -80°C. Samples were thawed at room temperature, sonicated at 80°C for 15 minutes and frozen again. This cycle was repeated 3 times to ensure homogeneity and samples were returned to -80°C pending analysis.
- a ⁇ levels were evaluated in plasma and brain samples by ELISA using Human A/340 and A/342 Fluorometiic ELISA kits from Biosource (Cat. No. 89-344 and 89-348) according to manufacturer's recommended procedures. In short, samples were thawed at room temperature, sonicated for 5 minutes at 80°C (sonication for brain homogenates; no sonication for plasma samples) and kept on ice. A ⁇ peptides were captured using 100 ⁇ l of the diluted samples to the plate and incubated without shaking at 4°C overnight. The samples were aspirated and the wells were rinsed 4 times with wash buffer obtained from the Biosource ELISA kit.
- the anti-A ⁇ 40 or anti-A ⁇ 42 rabbit polyclonal antiserum (specific for the A ⁇ 40 or A ⁇ 42 peptide) was added (100 ⁇ l) and the plate was incubated at room temperature for 2 hours with shaking. The wells were aspirated and washed 4 times before adding 100 ⁇ l of the alkaline phosphatase labeled anti-rabbit antibody and incubating at room temperature for 2 hours with shaking. The plates were then rinsed 5 times and the fluorescent substrate (100 ⁇ l) was added to the plate. The plate was incubated for 35 minutes at room temperature and the plate was read using a titer plate reader at an excitation wavelength of 460 nm and emission at 560 nm.
- increases in the levels of A ⁇ (relative to untreated control) of 20 to 39% are scored as “+”; increases of 40 to 69% are scored as “++”; and increases of 70% or higher are scored as “+ + +”.
- increases in the levels of A ⁇ of 5 to 19% are scored as “-”; decreases of 20 to 38% are scored as “- -”; and decreases of 39%> or more are scored as "- - -”.
- the tables show levels of A/3 peptides in the plasma and brain of TgCRND8 mice treated for 14 and 28 days with compounds of the invention.
- Tables 6 A and 6C show the data from Day 14 and Day 28 for the Plasma Vehicle group, respectively.
- Tables 6B and 7 show the data for the Plasma Methylcellulose group on Days 14 and 28, respectively.
- Tables 8 and 10 show the data on Days 14 and 28 for the Brain homogenate vehicle group, respectively.
- Tables 9 and 11 show the data for brain homogenate for the Methylcellulose group on Days 14 and 28, respectively.
- TABLE 6A Plasma Vehicle Group, Day 14
- ** fhe e ff ec t of this compound in the brain has only been tested on its ability to modulate the total levels of A ⁇ 40 and A ⁇ 42 peptides rather than measuring soluble and insoluble levels independently.
- AD Alzheimer Disease
- NAC non-amyloid component
- NAC is a 35 amino acid long peptide with highly hydrophobic stretches which can self-aggregate and form fibrils in vitro. Moreover, these fibrils can efficiently seed the formation of A ⁇ fibrils in vitro (Han, et al. 1995. Chem Biol.2: 163-169; Iwai, et al. 1995. Biochemistry 34: 10139). It is in fact through its NAC domain that alpha-synuclein retains its fibrillogenic properties.
- Modulating the properties of NAC or targeting NAC with the compounds of the invention could therefore be a valid therapeutic avenue to inhibit the formation of protein aggregates and inclusions associated with alpha-synucleopathies, as well as the formation of aggregates between the beta-amyloid peptide and NAC of alpha-synuclein.
- the ability of the compounds of the present invention to bind to NAC peptide in aqueous solution was evaluated.
- the binding ability conelates to the intensities of the peptide-compound complex peaks observed by the Electrospray Mass Spectrum.
- Millipore distilled deionized water was used to prepare all aqueous solutions.
- a Beckman ⁇ 36 pH meter fitted with a Corning Semi-Micro Combination pH Electrode was employed for pH determination.
- NAC (MW 3260.6 Da) at 20 ⁇ M was first analyzed at pH 7.40 and the usual sodium clusters was observed at +2, +3 and +4 at m/z 1335.5, 1116.7 and 843.4 respectively.
- the optimal cone voltage was determined to be 20V. i
- Mass spectrometry- Mass spectrometric analysis was performed using a Waters ZQ 4000 mass spectrometer equipped with a Waters 2795 sample manager. MassLynx 4.0 (earlier by MassLynx 3.5) was used for data processing and analysis. Test compounds were mixed with disaggregated peptides in aqueous media (6.6% EtOH) at a 5:1 ratio (20 ⁇ M NAC : 100 ⁇ M of test compound or 40 ⁇ M NAC : 200 ⁇ M of test compound). The pH of the mixture was adjusted to 7.4 ( ⁇ 0.2) using 0.1% NaOH (3-5 ⁇ L). Periodically, NAC peptide solution at 20 ⁇ M or 40 ⁇ M was also prepared in the same fashion and run as control.
- the spectra were obtained by introducing the solutions to the electrospray source by direct infusion using a syringe pump at a flow rate of 25 ⁇ l/min, and scanning from 100 to 2100 Da in the positive mode.
- the scan time was 0.9 sec per scan with an inter-scan delay of 0.1 sec and the run time was 5 min for each sample. All the mass spectra were sum of 300 scans.
- the desolvation and source temperature was 70°C and the cone and capillary voltage were maintained at 20 V and 3.2 kV respectively.
- the total area under the peaks for the bound NAC-compound complex divided by total area under the peaks for unbound NAC was determined for each compound tested. The results are summarized in Table 12 below
- the present invention also relates to novel compounds and the synthesis thereof. Accordingly, the following examples are presented to illustrate how some of those compounds may be prepared.
- Activated charcoal (1 g) was added and the resulting mixture was stirred for 30 minutes.
- the insoluble material was removed by filtration through a pad of Celite.
- the Celite-pad was washed with hot methanol (4 x 30 mL).
- the filtrate and the washings were combined, and concentrated to a thick-paste.
- Absolute ethanol (100 mL) and methanol (10 mL) were added; and the mixture was heated under reflux for 15 minutes.
- the mixture was cooled with an ice-bath.
- the solid was collected by filtration, rinsed washed 90%> ethanol (30 mL), absolute ethanol (3 x 30 mL), air-dried for 10 minutes, and dried in vacuo.
- the solid was suspended in absolute ethanol (100 mL); and the mixture was heated to reflux. Dropwise addition of water (65 mL) to the alcoholic mixture resulted complete dissolution of the solid. The solution was cooled slowly to room temperature with stirring under nitrogen overnight. The mixture was cooled with an ice-bath. The solid was collected by filtration, rinsed washed 90% ethanol (30 mL), absolute ethanol (3 x 30 mL), air-dried for 10 minutes, and ftirther dried in vacuo; affording compound BT as a cream colored crystalline solid (11.88 g, 33% yield). The 1H and 13 C NMR were consistent with the structure.
- the DL-2-amino-l-pentanol (10 g, 94 mmol) was added to a solution of 1,3- propane sultone (12.6 g, 100 mmol) in 2-butanone (95 mL). The mixture was heated to reflux for 3.5h. The mixture was cooled to room temperature overnight, and futher cooled in an ice-bath. The solid was collected by filtration, rinsed with cold THF. The material was air-dried for 20 minutes (15 g). The solid was suspended in absolute ethanol (80 mL) and the mixture was heated to reflux for lh. The mixture was cooled in an ice-bath; and the solid was collected by filtration, rinsed with cold ethanol. The material was air-dried for 15 minutes then at 60 °C in the vacuum oven overnight. Compound CAwas obtained as a fine white powder (14.49 g, 68%>). The 1H and 13 C NMR were consistent with the structure.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Indole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004249527A AU2004249527A1 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
MXPA05013977A MXPA05013977A (es) | 2003-06-23 | 2004-06-21 | Metodos y composiciones para tratar enfermedades relacionadas con amiloide. |
CA002529256A CA2529256A1 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
JP2006516597A JP2007516938A (ja) | 2003-06-23 | 2004-06-21 | アミロイド関連疾患を治療するための方法および組成物 |
EP04743998A EP1658264A2 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US48090603P | 2003-06-23 | 2003-06-23 | |
US60/480,906 | 2003-06-23 | ||
US51204703P | 2003-10-17 | 2003-10-17 | |
US60/512,047 | 2003-10-17 | ||
US10/871,514 US7414076B2 (en) | 2003-06-23 | 2004-06-18 | Methods and compositions for treating amyloid-related diseases |
US10/871,365 | 2004-06-18 | ||
US10/871,365 US7244764B2 (en) | 2003-06-23 | 2004-06-18 | Methods and compositions for treating amyloid-related diseases |
US10/871,514 | 2004-06-18 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2004113277A2 true WO2004113277A2 (en) | 2004-12-29 |
WO2004113277A8 WO2004113277A8 (en) | 2005-07-14 |
WO2004113277A3 WO2004113277A3 (en) | 2005-10-13 |
Family
ID=33545555
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/002337 WO2004113277A2 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
PCT/IB2004/002375 WO2004113275A2 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/002375 WO2004113275A2 (en) | 2003-06-23 | 2004-06-21 | Methods and compositions for treating amyloid-related diseases |
Country Status (12)
Country | Link |
---|---|
EP (2) | EP1644325A2 (ko) |
JP (2) | JP5146714B2 (ko) |
KR (1) | KR101124935B1 (ko) |
AU (2) | AU2004249529A1 (ko) |
BR (1) | BRPI0411743A (ko) |
CA (2) | CA2529256A1 (ko) |
EA (1) | EA012429B1 (ko) |
MX (2) | MXPA05013977A (ko) |
NO (1) | NO335084B1 (ko) |
NZ (1) | NZ544684A (ko) |
UA (1) | UA96115C2 (ko) |
WO (2) | WO2004113277A2 (ko) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007118276A1 (en) * | 2006-04-14 | 2007-10-25 | Prana Biotechnology Ltd | Method of treatment of age-related macular degeneration(amd) |
US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
KR101173677B1 (ko) * | 2009-12-11 | 2012-08-13 | 한국과학기술연구원 | Epps를 유효성분으로 함유하는 베타아밀로이드 집적 관련 질환의 예방 또는 치료용 약학적 조성물 |
US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
US8748656B2 (en) | 2006-10-12 | 2014-06-10 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
EP3424502A4 (en) * | 2016-03-04 | 2020-01-08 | Niigata University | AQUAPORIN-4 FUNCTION PROMOTER AND PHARMACEUTICAL COMPOSITION FOR NEUROLOGICAL DISEASES |
CN112912732A (zh) * | 2018-08-03 | 2021-06-04 | 香港大学 | 用于淀粉样蛋白原纤维、淀粉样蛋白斑块、rna和核仁的检测和成像的组合物和方法 |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
WO2022148457A1 (en) * | 2021-01-11 | 2022-07-14 | Helios Huaming Biopharma Co., Ltd. | Substituted salicylamide compounds and use thereof |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2011250847B2 (en) * | 2003-06-23 | 2013-06-20 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
EP1644325A2 (en) * | 2003-06-23 | 2006-04-12 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
AU2005310979A1 (en) * | 2004-11-16 | 2006-06-08 | Bellus Health (International) Limited | Compounds for the treatment of CNS and amyloid associated diseases |
JP2009510050A (ja) * | 2005-09-30 | 2009-03-12 | ベルス ヘルス (インターナショナル) リミティッド | カルボキシアルキルスルホン酸を含む薬学的組成物および方法 |
KR100883132B1 (ko) | 2006-10-24 | 2009-02-10 | 재단법인서울대학교산학협력재단 | 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체에선택적으로 작용하는 절단제 |
WO2008133779A2 (en) | 2007-03-07 | 2008-11-06 | Massachusetts Institute Of Technology | Functionalization of nanoscale articles including nanotubes and fullerenes |
WO2008122030A2 (en) * | 2007-04-02 | 2008-10-09 | University Of South Alabama | Carbon dioxide scrubbing using ionic materials |
DK2247558T3 (da) | 2008-02-14 | 2022-02-21 | Lilly Co Eli | Nye billeddannelsesmidler til detektering af neurologisk dysfunktion |
WO2009136978A2 (en) | 2008-03-04 | 2009-11-12 | Massachusetts Institute Of Technology | Devices and methods for determination of species including chemical warfare agents |
JP5650642B2 (ja) | 2008-08-01 | 2015-01-07 | バイオキシネス ファーマシューティカルズ, インコーポレイテッド | メチオニンアナログおよびそれらを使用する方法 |
CN102170882B (zh) * | 2008-08-29 | 2014-04-02 | 特温蒂斯公司 | 治疗淀粉状蛋白疾病的组合物和其制药用途 |
US8735313B2 (en) | 2008-12-12 | 2014-05-27 | Massachusetts Institute Of Technology | High charge density structures, including carbon-based nanostructures and applications thereof |
US8456073B2 (en) | 2009-05-29 | 2013-06-04 | Massachusetts Institute Of Technology | Field emission devices including nanotubes or other nanoscale articles |
WO2011017800A1 (en) | 2009-08-10 | 2011-02-17 | Bellus Health (International) Limited | Methods, compounds, and compositions for delivering 1,3-propan ed isulfonic acid |
WO2011044221A2 (en) | 2009-10-06 | 2011-04-14 | Massachusetts Institute Of Technology | Method and apparatus for determining radiation |
US8772537B2 (en) * | 2010-07-28 | 2014-07-08 | Sumitomo Chemical Company, Limited | Process for producing aminoalkylthiosulfuric acid compound |
WO2012061607A2 (en) | 2010-11-03 | 2012-05-10 | Massachusetts Institute Of Technology | Compositions comprising functionalized carbon-based nanostructures and related methods |
JP6928385B2 (ja) * | 2015-08-10 | 2021-09-01 | アルジオン, インコーポレイテッド | 神経変性疾患を治療および予防するための組成物および方法 |
JP6675167B2 (ja) * | 2015-08-28 | 2020-04-01 | シスメックス株式会社 | ペプチドの遊離方法及び回収方法、並びにペプチド遊離剤及び試薬キット |
US9556301B1 (en) | 2015-12-02 | 2017-01-31 | King Fahd Universoty of Petroleum and Minerals | Cyclopolymer containing residues of methionine and synthesis and uses thereof |
RU2657844C1 (ru) * | 2017-01-09 | 2018-06-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Осетинская государственная медицинская академия" Министерства здравоохранения Российской Федерации | Способ лечения экспериментальной амилоидной кардиопатии у крыс |
WO2019090323A1 (en) | 2017-11-06 | 2019-05-09 | Massachusetts Institute Of Technology | High functionalization density graphene |
JP2022059674A (ja) * | 2020-10-02 | 2022-04-14 | 国立大学法人高知大学 | アミロイドβの凝集抑制剤、アミロイドβ凝集疾患用医薬組成物、およびその用途 |
EP3992182A1 (en) | 2020-10-28 | 2022-05-04 | Cisbio Bioassays | Europium(iii) complexes as ph sensors |
CN113433325A (zh) * | 2021-06-07 | 2021-09-24 | 西安市第一医院 | 血清vitronectin在AL型淀粉样变的诊断及疾病分期中的应用 |
WO2023212289A1 (en) | 2022-04-28 | 2023-11-02 | Alzheon, Inc. | Tramiprosate for treating apoe4-related diseases |
WO2024119183A1 (en) | 2022-12-02 | 2024-06-06 | Alzheon, Inc. | Methods for treating neurodegenerative disorders with tramiprosate |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE927992C (de) * | 1952-07-27 | 1955-05-23 | Hoechst Ag | Verfahren zur Herstellung von Salzen des 1, 2-Dimethyl-3-phenyl-4-amino-5-pyrazolons |
DE2140278A1 (en) * | 1970-01-19 | 1972-03-09 | Crompton and Knowles Corp., Worcester, Mass. (V.St.A.) | Water-soluble dyes and dye intermediates |
US4085134A (en) * | 1974-02-15 | 1978-04-18 | Petrolite Corporation | Amino-phosphonic-sulfonic acids |
WO1996028187A1 (en) * | 1995-03-15 | 1996-09-19 | Queen's University At Kingston | Method for treating amyloidosis |
WO1997014306A1 (en) * | 1995-10-17 | 1997-04-24 | Dovetail Technologies, Inc. | Low molecular weight cell, bone marrow and immune stimulants |
WO2000064420A2 (en) * | 1999-04-28 | 2000-11-02 | Queen's University At Kingston | Compositions and methods for treating amyloidosis using sulphonate derivatives |
WO2000071101A2 (en) * | 1999-05-24 | 2000-11-30 | Queen's University At Kingston | Methods and compounds for inhibiting amyloid deposits |
WO2001003680A2 (en) * | 1999-07-09 | 2001-01-18 | Isis Innovation Limited | Compounds for inhibiting diseases and preparing cells for transplantation |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2376911A (en) * | 1941-12-24 | 1945-05-29 | Swiss Company Of Soc Of Chemic | Derivatives of sulphonated amines and process of preparing same |
US3453309A (en) * | 1966-10-14 | 1969-07-01 | Parke Davis & Co | Phenylalkylaminoethyl thiosulfates |
JPS60184564A (ja) * | 1984-03-05 | 1985-09-20 | Mitsui Toatsu Chem Inc | 液晶に使用するジスアゾ系二色性染料、該染料を含む液晶組成物及び表示装置 |
DD287256A5 (de) * | 1989-08-21 | 1991-02-21 | Akademie Der Wissenschaften Der Ddr,De | Verfahren zur herstellung von chiralen wasserloeslichen ammoniumalkansulfonsaeuren sowie deren salzen und sulfobetainen |
JP3068841B2 (ja) * | 1990-08-23 | 2000-07-24 | 日本臓器製薬株式会社 | アミノアルカンスルホン酸誘導体を有効成分として含有する心疾患治療剤 |
JP3070687B2 (ja) * | 1990-07-19 | 2000-07-31 | 日本臓器製薬株式会社 | 心疾患治療剤 |
FR2665444B1 (fr) * | 1990-08-06 | 1992-11-27 | Sanofi Sa | Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant. |
JPH0995444A (ja) * | 1995-10-02 | 1997-04-08 | Teijin Ltd | アミロイド蛋白凝集阻害剤 |
AU7237198A (en) * | 1997-05-21 | 1998-12-11 | Shionogi & Co., Ltd. | Remedies for dementia of alzheimer type containing gamma-sultam derivatives |
EP1159263A1 (en) * | 1999-02-26 | 2001-12-05 | Merck & Co., Inc. | Novel sulfonamide compounds and uses thereof |
JP4440446B2 (ja) * | 1999-10-05 | 2010-03-24 | 花王株式会社 | 皮膚外用剤 |
US20020094335A1 (en) * | 1999-11-29 | 2002-07-18 | Robert Chalifour | Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases |
CN1433321A (zh) * | 1999-11-29 | 2003-07-30 | 尼奥切姆公司 | 预防和治疗Alzheimer症和其他与淀粉样蛋白有关的疾病的疫苗 |
EP1251837A2 (en) * | 1999-12-23 | 2002-10-30 | Neurochem, Inc. | Compounds and methods for modulating cerebral amyloid angiopathy |
US20020115717A1 (en) * | 2000-07-25 | 2002-08-22 | Francine Gervais | Amyloid targeting imaging agents and uses thereof |
WO2004058239A1 (en) * | 2002-12-24 | 2004-07-15 | Neurochem (International) Limited | Therapeutic formulations for the treatment of beta-amyloid related diseases |
EP1644325A2 (en) * | 2003-06-23 | 2006-04-12 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
-
2004
- 2004-06-21 EP EP04744034A patent/EP1644325A2/en not_active Withdrawn
- 2004-06-21 MX MXPA05013977A patent/MXPA05013977A/es unknown
- 2004-06-21 WO PCT/IB2004/002337 patent/WO2004113277A2/en active Application Filing
- 2004-06-21 UA UAA200600637A patent/UA96115C2/uk unknown
- 2004-06-21 CA CA002529256A patent/CA2529256A1/en not_active Abandoned
- 2004-06-21 JP JP2006516599A patent/JP5146714B2/ja not_active Expired - Fee Related
- 2004-06-21 NZ NZ544684A patent/NZ544684A/en not_active IP Right Cessation
- 2004-06-21 WO PCT/IB2004/002375 patent/WO2004113275A2/en active Application Filing
- 2004-06-21 EA EA200600078A patent/EA012429B1/ru not_active IP Right Cessation
- 2004-06-21 JP JP2006516597A patent/JP2007516938A/ja active Pending
- 2004-06-21 CA CA2529257A patent/CA2529257C/en not_active Expired - Fee Related
- 2004-06-21 EP EP04743998A patent/EP1658264A2/en not_active Withdrawn
- 2004-06-21 AU AU2004249529A patent/AU2004249529A1/en not_active Abandoned
- 2004-06-21 BR BRPI0411743-3A patent/BRPI0411743A/pt not_active IP Right Cessation
- 2004-06-21 KR KR1020057024647A patent/KR101124935B1/ko not_active IP Right Cessation
- 2004-06-21 MX MXPA05014166A patent/MXPA05014166A/es active IP Right Grant
- 2004-06-21 AU AU2004249527A patent/AU2004249527A1/en not_active Abandoned
-
2005
- 2005-12-12 NO NO20055894A patent/NO335084B1/no not_active IP Right Cessation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE927992C (de) * | 1952-07-27 | 1955-05-23 | Hoechst Ag | Verfahren zur Herstellung von Salzen des 1, 2-Dimethyl-3-phenyl-4-amino-5-pyrazolons |
DE2140278A1 (en) * | 1970-01-19 | 1972-03-09 | Crompton and Knowles Corp., Worcester, Mass. (V.St.A.) | Water-soluble dyes and dye intermediates |
US4085134A (en) * | 1974-02-15 | 1978-04-18 | Petrolite Corporation | Amino-phosphonic-sulfonic acids |
WO1996028187A1 (en) * | 1995-03-15 | 1996-09-19 | Queen's University At Kingston | Method for treating amyloidosis |
WO1997014306A1 (en) * | 1995-10-17 | 1997-04-24 | Dovetail Technologies, Inc. | Low molecular weight cell, bone marrow and immune stimulants |
WO2000064420A2 (en) * | 1999-04-28 | 2000-11-02 | Queen's University At Kingston | Compositions and methods for treating amyloidosis using sulphonate derivatives |
WO2000071101A2 (en) * | 1999-05-24 | 2000-11-30 | Queen's University At Kingston | Methods and compounds for inhibiting amyloid deposits |
WO2001003680A2 (en) * | 1999-07-09 | 2001-01-18 | Isis Innovation Limited | Compounds for inhibiting diseases and preparing cells for transplantation |
Non-Patent Citations (15)
Title |
---|
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314317 Database accession no. BRN 4261672 & ISKANDER MN ET AL.: EUR. J. MED. CHEM. CHIM. THER., vol. 26, no. 2, 1991, pages 129-136, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314318 Database accession no. BRN 7023352 & CAMPAGNA F. ET AL.: FARMACO, vol. 49, no. 10, 1994, pages 653-58, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314319 Database accession no. BRN 8919306 & KILLDAY K. B. ET AL.: J. NAT. PROD., vol. 64, no. 4, 2001, pages 525-526, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314320 Database accession no. BRN 6023409 & TOMSON ET AL.: J. APPL. CHEM. USSR, ENGL. TRANSL., vol. 57, no. 9, 1984, pages 1885-91, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314321 Database accession no. BRN 2272192 & WOOD. J. M. ET AL.: J. CHEM. SOC. PERKIN TRANS 2, 5, 2002, pages 938-46, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314323 Database accession no. BRN 1712477 & ABDERHALDEN; RIESZ: FERMENTFORSCHUNG, 12, 1930, page 198, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314324 Database accession no. BRN 2972476 & DORN, WALTER: Z. CHEM., 7, 1967, page 151, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314325 Database accession no. BRN 2434022 & JUSTUS LIEBIGS ANN. CHEM., 647, 1961, pages 37-40, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314326 Database accession no. BRN 5620601 & IENAGA, KAZUHARA ET AL.: CHEM. PHARM. BULL., vol. 36, no. 8, 1988, pages 2796-2801, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314327 Database accession no. BRN 2846394 & IIDA ET AL.: KOGYO KAGAKU ZASSHI, 72, 1969, page 887, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314328 Database accession no. BRN 3952462, 3935697 & ALLEN ET AL.: ANAL. CHEM., 37, 1965, page 156, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314329 Database accession no. BRN5568774 & IENAGA, KAZUHARA ET AL.: CHEM. PHARM. BULL., vol. 36, no. 1, 1988, pages 70-77, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002318687 Database accession no. BRN 3388511 & NOSEK ET AL.: CHEM. LISTY, 46, 1956, page 672, * |
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002318688 Database accession no. BRN 3948718 & B. HELFERICH, K. H. HERMANN: JUSTUS LIEBIGS ANN. CHEM., 651, 1962, pages 33-42, * |
MIMURA T ET AL: "A NOVEL CLASS OF ENKEPHALINASE INHIBITORS CONTAINING A C-TERMINAL SULFO GROUP" JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 3, 7 February 1992 (1992-02-07), pages 602-608, XP000611537 ISSN: 0022-2623 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
US8835654B2 (en) | 2004-12-22 | 2014-09-16 | Bhi Limited Partnership | Method and compositions for treating amyloid-related diseases |
US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
WO2007118276A1 (en) * | 2006-04-14 | 2007-10-25 | Prana Biotechnology Ltd | Method of treatment of age-related macular degeneration(amd) |
US9163018B2 (en) | 2006-04-14 | 2015-10-20 | Prana Biotechnology Inc. | Method of treatment of age-related macular degeneration (AMD) |
US10238611B2 (en) | 2006-10-12 | 2019-03-26 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
US8748656B2 (en) | 2006-10-12 | 2014-06-10 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
US10857109B2 (en) | 2006-10-12 | 2020-12-08 | Bellus Health, Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
US11020360B2 (en) | 2006-10-12 | 2021-06-01 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
US8536178B2 (en) | 2009-12-11 | 2013-09-17 | Korea Institute Of Science And Technology | Pharmaceutical composition for preventing or treating diseases associated with beta-amyloid accumulation containing morpholin or piperazine based compounds having SO3H or COOH as active ingredient |
KR101173677B1 (ko) * | 2009-12-11 | 2012-08-13 | 한국과학기술연구원 | Epps를 유효성분으로 함유하는 베타아밀로이드 집적 관련 질환의 예방 또는 치료용 약학적 조성물 |
EP3424502A4 (en) * | 2016-03-04 | 2020-01-08 | Niigata University | AQUAPORIN-4 FUNCTION PROMOTER AND PHARMACEUTICAL COMPOSITION FOR NEUROLOGICAL DISEASES |
US10632084B2 (en) | 2016-03-04 | 2020-04-28 | Niigata University | Aquaporin 4 function promotor and pharmaceutical composition for neurological disorders |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
CN112912732A (zh) * | 2018-08-03 | 2021-06-04 | 香港大学 | 用于淀粉样蛋白原纤维、淀粉样蛋白斑块、rna和核仁的检测和成像的组合物和方法 |
WO2022148457A1 (en) * | 2021-01-11 | 2022-07-14 | Helios Huaming Biopharma Co., Ltd. | Substituted salicylamide compounds and use thereof |
Also Published As
Publication number | Publication date |
---|---|
BRPI0411743A (pt) | 2006-08-08 |
EA012429B1 (ru) | 2009-10-30 |
WO2004113275A3 (en) | 2005-10-27 |
KR101124935B1 (ko) | 2012-04-12 |
NO335084B1 (no) | 2014-09-08 |
CA2529257A1 (en) | 2004-12-29 |
CA2529257C (en) | 2013-04-23 |
NZ544684A (en) | 2009-10-30 |
JP2007516939A (ja) | 2007-06-28 |
AU2004249529A1 (en) | 2004-12-29 |
NO20055894L (no) | 2006-03-21 |
EP1658264A2 (en) | 2006-05-24 |
WO2004113277A8 (en) | 2005-07-14 |
CA2529256A1 (en) | 2004-12-29 |
MXPA05014166A (es) | 2006-03-13 |
JP5146714B2 (ja) | 2013-02-20 |
WO2004113275A2 (en) | 2004-12-29 |
EA200600078A1 (ru) | 2006-08-25 |
UA96115C2 (uk) | 2011-10-10 |
MXPA05013977A (es) | 2006-03-09 |
KR20060023172A (ko) | 2006-03-13 |
EP1644325A2 (en) | 2006-04-12 |
WO2004113277A3 (en) | 2005-10-13 |
JP2007516938A (ja) | 2007-06-28 |
AU2004249527A1 (en) | 2004-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7244764B2 (en) | Methods and compositions for treating amyloid-related diseases | |
WO2004113277A2 (en) | Methods and compositions for treating amyloid-related diseases | |
EP1836161B1 (en) | Methods and compositions for treating amyloid-related diseases | |
US8642801B2 (en) | Methods and compositions for treating amyloid-related diseases | |
US7414076B2 (en) | Methods and compositions for treating amyloid-related diseases | |
US20060167057A1 (en) | Compounds for the treatment of CNS and amyloid associated diseases | |
US20060183800A1 (en) | Methods and fluorinated compositions for treating amyloid-related diseases | |
US20050038000A1 (en) | Methods and compositions for the treatment of amyloid-and epileptogenesis-associated diseases | |
AU2004251717B2 (en) | Treatment of amyloid- and epileptogenesis-associated diseases | |
AU2011250847B2 (en) | Methods and compositions for treating amyloid-related diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480024250.3 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
CFP | Corrected version of a pamphlet front page | ||
CR1 | Correction of entry in section i |
Free format text: IN PCT GAZETTE 53/2004 UNDER (72, 75) REPLACE "KONG, YIANQI" BY "KONG, XIANQI" |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004249527 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2529256 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2005/013977 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2004249527 Country of ref document: AU Date of ref document: 20040621 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004249527 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006516597 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004743998 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 544682 Country of ref document: NZ |
|
WWP | Wipo information: published in national office |
Ref document number: 2004743998 Country of ref document: EP |