JP7478252B2 - Sarm1の阻害剤 - Google Patents
Sarm1の阻害剤 Download PDFInfo
- Publication number
- JP7478252B2 JP7478252B2 JP2022561466A JP2022561466A JP7478252B2 JP 7478252 B2 JP7478252 B2 JP 7478252B2 JP 2022561466 A JP2022561466 A JP 2022561466A JP 2022561466 A JP2022561466 A JP 2022561466A JP 7478252 B2 JP7478252 B2 JP 7478252B2
- Authority
- JP
- Japan
- Prior art keywords
- optionally substituted
- nitrogen
- aliphatic
- sulfur
- independently selected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 101000685982 Homo sapiens NAD(+) hydrolase SARM1 Proteins 0.000 title claims description 99
- 102100023356 NAD(+) hydrolase SARM1 Human genes 0.000 title claims description 99
- 239000003112 inhibitor Substances 0.000 title description 52
- 150000001875 compounds Chemical class 0.000 claims description 287
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 242
- 229910052757 nitrogen Inorganic materials 0.000 claims description 151
- 125000005842 heteroatom Chemical group 0.000 claims description 133
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 131
- 239000011593 sulfur Chemical group 0.000 claims description 131
- 229910052717 sulfur Chemical group 0.000 claims description 131
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 126
- 239000001301 oxygen Substances 0.000 claims description 126
- 229910052760 oxygen Inorganic materials 0.000 claims description 126
- 230000003376 axonal effect Effects 0.000 claims description 84
- 230000007850 degeneration Effects 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 49
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 48
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 239000012472 biological sample Substances 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 description 170
- 239000000203 mixture Substances 0.000 description 168
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 110
- 229920006395 saturated elastomer Polymers 0.000 description 73
- 125000000623 heterocyclic group Chemical group 0.000 description 69
- 230000004770 neurodegeneration Effects 0.000 description 65
- 201000010099 disease Diseases 0.000 description 59
- 208000014674 injury Diseases 0.000 description 52
- 230000006378 damage Effects 0.000 description 50
- 208000035475 disorder Diseases 0.000 description 49
- 208000015122 neurodegenerative disease Diseases 0.000 description 49
- 125000002619 bicyclic group Chemical group 0.000 description 47
- 208000033808 peripheral neuropathy Diseases 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- 208000027418 Wounds and injury Diseases 0.000 description 42
- 230000000694 effects Effects 0.000 description 42
- -1 bicyclic hydrocarbon Chemical class 0.000 description 40
- 125000003118 aryl group Chemical group 0.000 description 38
- 229910052736 halogen Inorganic materials 0.000 description 37
- 150000002367 halogens Chemical class 0.000 description 37
- 125000002950 monocyclic group Chemical group 0.000 description 37
- 201000001119 neuropathy Diseases 0.000 description 35
- 230000007823 neuropathy Effects 0.000 description 35
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 34
- 239000003814 drug Substances 0.000 description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 32
- 239000000090 biomarker Substances 0.000 description 32
- 150000001721 carbon Chemical group 0.000 description 32
- 229910052799 carbon Inorganic materials 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 31
- 125000001072 heteroaryl group Chemical group 0.000 description 31
- 239000000523 sample Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 238000003556 assay Methods 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 210000002569 neuron Anatomy 0.000 description 22
- 210000003050 axon Anatomy 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 20
- 150000002431 hydrogen Chemical class 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 230000007845 axonopathy Effects 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- 210000003169 central nervous system Anatomy 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 230000000472 traumatic effect Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 125000004093 cyano group Chemical group *C#N 0.000 description 15
- 229940124597 therapeutic agent Drugs 0.000 description 15
- 208000017667 Chronic Disease Diseases 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 101710134519 Nicotinamide riboside kinase 1 Proteins 0.000 description 13
- 102100029562 Nicotinamide riboside kinase 1 Human genes 0.000 description 13
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 13
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 238000000338 in vitro Methods 0.000 description 13
- 208000030159 metabolic disease Diseases 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 208000028389 Nerve injury Diseases 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 12
- 230000008764 nerve damage Effects 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 208000024827 Alzheimer disease Diseases 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 208000018737 Parkinson disease Diseases 0.000 description 11
- 208000030886 Traumatic Brain injury Diseases 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 210000003594 spinal ganglia Anatomy 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 208000016192 Demyelinating disease Diseases 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 230000001537 neural effect Effects 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 9
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 9
- 208000012902 Nervous system disease Diseases 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 201000006417 multiple sclerosis Diseases 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 description 8
- 208000025966 Neurological disease Diseases 0.000 description 8
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 description 8
- 229910004298 SiO 2 Inorganic materials 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 238000002512 chemotherapy Methods 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 230000007557 neuronal destruction Effects 0.000 description 8
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 208000011580 syndromic disease Diseases 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 230000009529 traumatic brain injury Effects 0.000 description 8
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 208000002720 Malnutrition Diseases 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 206010014599 encephalitis Diseases 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 208000028867 ischemia Diseases 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 210000001428 peripheral nervous system Anatomy 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 208000030090 Acute Disease Diseases 0.000 description 6
- 102100037738 Fatty acid-binding protein, heart Human genes 0.000 description 6
- 101710136552 Fatty acid-binding protein, heart Proteins 0.000 description 6
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 6
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 6
- 206010061323 Optic neuropathy Diseases 0.000 description 6
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 6
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 208000006011 Stroke Diseases 0.000 description 6
- 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 6
- 229930006000 Sucrose Natural products 0.000 description 6
- 229940122803 Vinca alkaloid Drugs 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 208000016097 disease of metabolism Diseases 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000000626 neurodegenerative effect Effects 0.000 description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 208000020911 optic nerve disease Diseases 0.000 description 6
- 210000000578 peripheral nerve Anatomy 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 208000030507 AIDS Diseases 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 208000037157 Azotemia Diseases 0.000 description 5
- 206010010356 Congenital anomaly Diseases 0.000 description 5
- BQOHYSXSASDCEA-KEOHHSTQSA-N Cyclic ADP-Ribose Chemical compound C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C=2N=CN3C(C=2N=C1)=N)O)O)OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H]3O1 BQOHYSXSASDCEA-KEOHHSTQSA-N 0.000 description 5
- 206010014612 Encephalitis viral Diseases 0.000 description 5
- 208000010412 Glaucoma Diseases 0.000 description 5
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 5
- 208000023105 Huntington disease Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 102000002250 NAD+ Nucleosidase Human genes 0.000 description 5
- 108010000193 NAD+ Nucleosidase Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 229940079156 Proteasome inhibitor Drugs 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 229940123237 Taxane Drugs 0.000 description 5
- 206010002022 amyloidosis Diseases 0.000 description 5
- 201000007058 anterior ischemic optic neuropathy Diseases 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 229930013356 epothilone Natural products 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 208000012268 mitochondrial disease Diseases 0.000 description 5
- 108010090677 neurofilament protein L Proteins 0.000 description 5
- 235000018343 nutrient deficiency Nutrition 0.000 description 5
- 230000009518 penetrating injury Effects 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003207 proteasome inhibitor Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 230000002207 retinal effect Effects 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 208000009852 uremia Diseases 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 5
- 229960004528 vincristine Drugs 0.000 description 5
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 5
- 201000002498 viral encephalitis Diseases 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- 206010003591 Ataxia Diseases 0.000 description 4
- 208000000412 Avitaminosis Diseases 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 208000018380 Chemical injury Diseases 0.000 description 4
- 206010012305 Demyelination Diseases 0.000 description 4
- 201000011240 Frontotemporal dementia Diseases 0.000 description 4
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 4
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000001089 Multiple system atrophy Diseases 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 206010047627 Vitamin deficiencies Diseases 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 208000027137 acute motor axonal neuropathy Diseases 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 230000001908 autoinhibitory effect Effects 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 208000037584 hereditary sensory and autonomic neuropathy Diseases 0.000 description 4
- 208000008675 hereditary spastic paraplegia Diseases 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 208000005264 motor neuron disease Diseases 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 208000020431 spinal cord injury Diseases 0.000 description 4
- 208000002320 spinal muscular atrophy Diseases 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 3
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010000599 Acromegaly Diseases 0.000 description 3
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 3
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- 208000018652 Closed Head injury Diseases 0.000 description 3
- 206010011878 Deafness Diseases 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000010055 Globoid Cell Leukodystrophy Diseases 0.000 description 3
- 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 3
- 229930186217 Glycolipid Natural products 0.000 description 3
- 206010019196 Head injury Diseases 0.000 description 3
- 206010019663 Hepatic failure Diseases 0.000 description 3
- 206010019973 Herpes virus infection Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000028226 Krabbe disease Diseases 0.000 description 3
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 3
- 208000034800 Leukoencephalopathies Diseases 0.000 description 3
- 208000026072 Motor neurone disease Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 206010056677 Nerve degeneration Diseases 0.000 description 3
- 108010088373 Neurofilament Proteins Proteins 0.000 description 3
- 102000008763 Neurofilament Proteins Human genes 0.000 description 3
- 102000001775 Neurogranin Human genes 0.000 description 3
- 108010015301 Neurogranin Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- 208000008601 Polycythemia Diseases 0.000 description 3
- 241000097929 Porphyria Species 0.000 description 3
- 208000010642 Porphyrias Diseases 0.000 description 3
- 208000024777 Prion disease Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000700584 Simplexvirus Species 0.000 description 3
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 206010073696 Wallerian degeneration Diseases 0.000 description 3
- PWJFNRJRHXWEPT-AOOZFPJJSA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2r,3r,4r)-2,3,4-trihydroxy-5-oxopentyl] hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)C=O)[C@@H](O)[C@H]1O PWJFNRJRHXWEPT-AOOZFPJJSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 3
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 3
- 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 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 238000004166 bioassay Methods 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012829 chemotherapy agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 3
- 210000003608 fece Anatomy 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 230000010370 hearing loss Effects 0.000 description 3
- 231100000888 hearing loss Toxicity 0.000 description 3
- 208000016354 hearing loss disease Diseases 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 208000003532 hypothyroidism Diseases 0.000 description 3
- 230000002989 hypothyroidism Effects 0.000 description 3
- 238000007913 intrathecal administration Methods 0.000 description 3
- 230000002262 irrigation Effects 0.000 description 3
- 238000003973 irrigation Methods 0.000 description 3
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 3
- 229960002014 ixabepilone Drugs 0.000 description 3
- 208000036546 leukodystrophy Diseases 0.000 description 3
- 208000007903 liver failure Diseases 0.000 description 3
- 231100000835 liver failure Toxicity 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 210000000066 myeloid cell Anatomy 0.000 description 3
- 229950006238 nadide Drugs 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 210000000944 nerve tissue Anatomy 0.000 description 3
- 201000002761 non-arteritic anterior ischemic optic neuropathy Diseases 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 210000001328 optic nerve Anatomy 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 3
- 208000035824 paresthesia Diseases 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 208000027232 peripheral nervous system disease Diseases 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 210000000225 synapse Anatomy 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229960003433 thalidomide Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000008736 traumatic injury Effects 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 3
- 229960004355 vindesine Drugs 0.000 description 3
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 3
- 230000008734 wallerian degeneration Effects 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- FWOPJXVQGMZKEP-UHFFFAOYSA-N 3-methyl-2h-indazole Chemical compound C1=CC=CC2=C(C)NN=C21 FWOPJXVQGMZKEP-UHFFFAOYSA-N 0.000 description 2
- 206010069754 Acquired gene mutation Diseases 0.000 description 2
- 208000032194 Acute haemorrhagic leukoencephalitis Diseases 0.000 description 2
- 201000011452 Adrenoleukodystrophy Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000011403 Alexander disease Diseases 0.000 description 2
- 201000002862 Angle-Closure Glaucoma Diseases 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
- 208000001827 Ataxia with vitamin E deficiency Diseases 0.000 description 2
- 102000014461 Ataxins Human genes 0.000 description 2
- 108010078286 Ataxins Proteins 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000006373 Bell palsy Diseases 0.000 description 2
- 102100022548 Beta-hexosaminidase subunit alpha Human genes 0.000 description 2
- 241000150347 Bunyavirales Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 101150009911 Ccl7 gene Proteins 0.000 description 2
- 206010008025 Cerebellar ataxia Diseases 0.000 description 2
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 description 2
- 208000004051 Chronic Traumatic Encephalopathy Diseases 0.000 description 2
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 2
- 206010062346 Congenital neuropathy Diseases 0.000 description 2
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 2
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 2
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 101150074775 Csf1 gene Proteins 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines 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
- 206010011903 Deafness traumatic Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010017076 Fracture Diseases 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 208000015872 Gaucher disease Diseases 0.000 description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 2
- 101000759926 Homo sapiens Ubiquitin carboxyl-terminal hydrolase isozyme L1 Proteins 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 206010021036 Hyponatraemia Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010022031 Inherited neuropathies Diseases 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- 201000002832 Lewy body dementia Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 2
- 206010056886 Mucopolysaccharidosis I Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 2
- 206010029240 Neuritis Diseases 0.000 description 2
- 208000014060 Niemann-Pick disease Diseases 0.000 description 2
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- 208000003435 Optic Neuritis Diseases 0.000 description 2
- 206010069350 Osmotic demyelination syndrome Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010033892 Paraplegia Diseases 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000027520 Somatoform disease Diseases 0.000 description 2
- 208000032930 Spastic paraplegia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 2
- 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- 208000022292 Tay-Sachs disease Diseases 0.000 description 2
- 102100025038 Ubiquitin carboxyl-terminal hydrolase isozyme L1 Human genes 0.000 description 2
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 2
- 241000710886 West Nile virus Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 2
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 108010044540 auristatin Proteins 0.000 description 2
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 208000009885 central pontine myelinolysis Diseases 0.000 description 2
- 239000013043 chemical agent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 238000010835 comparative analysis Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000037011 constitutive activity Effects 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 230000003436 cytoskeletal effect Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229940043239 cytotoxic antineoplastic drug Drugs 0.000 description 2
- 208000017004 dementia pugilistica Diseases 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 201000002491 encephalomyelitis Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000003883 epothilone derivatives Chemical class 0.000 description 2
- 229960000285 ethambutol Drugs 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 201000003264 familial isolated deficiency of vitamin E Diseases 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 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 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 2
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 208000010544 human prion disease Diseases 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007919 intrasynovial administration Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 208000027753 pain disease Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 210000004345 peroneal nerve Anatomy 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 description 2
- 201000011461 pre-eclampsia Diseases 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 201000006366 primary open angle glaucoma Diseases 0.000 description 2
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 230000037439 somatic mutation Effects 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 208000009174 transverse myelitis Diseases 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- HSNPBYKCCNMQNA-UHFFFAOYSA-N (4-chloro-3-fluorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(F)=C1 HSNPBYKCCNMQNA-UHFFFAOYSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- SNKPPKAANOYIRX-UHFFFAOYSA-N 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole Chemical compound CN1C=NC=C1B1OC(C)(C)C(C)(C)O1 SNKPPKAANOYIRX-UHFFFAOYSA-N 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 108091005508 Acid proteases Proteins 0.000 description 1
- 208000018126 Adrenomyeloneuropathy Diseases 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010060159 Apolipoprotein E4 Proteins 0.000 description 1
- 208000006400 Arbovirus Encephalitis Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000001992 Autosomal Dominant Optic Atrophy Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000008889 California Encephalitis Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 101150075117 Ccl12 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- 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 1
- 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 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010067601 Dysmyelination Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000792859 Enema Species 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
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 206010016880 Folate deficiency Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 108700005000 Glial Fibrillary Acidic Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 description 1
- 101001111338 Homo sapiens Neurofilament heavy polypeptide Proteins 0.000 description 1
- 101000979333 Homo sapiens Neurofilament light polypeptide Proteins 0.000 description 1
- 101000633302 Homo sapiens Nicotinamide riboside kinase 1 Proteins 0.000 description 1
- 101000996052 Homo sapiens Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 Proteins 0.000 description 1
- 208000015178 Hurler syndrome Diseases 0.000 description 1
- 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 description 1
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 description 1
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 201000009908 La Crosse encephalitis Diseases 0.000 description 1
- 241000713102 La Crosse virus Species 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 102000009030 Member 1 Subfamily D ATP Binding Cassette Transporter Human genes 0.000 description 1
- 108010049137 Member 1 Subfamily D ATP Binding Cassette Transporter Proteins 0.000 description 1
- 201000011442 Metachromatic leukodystrophy Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 102100026784 Myelin proteolipid protein Human genes 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 102100024007 Neurofilament heavy polypeptide Human genes 0.000 description 1
- 102100023057 Neurofilament light polypeptide Human genes 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 102100034451 Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 208000017493 Pelizaeus-Merzbacher disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010072005 Spinal pain Diseases 0.000 description 1
- 208000010112 Spinocerebellar Degenerations Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101150044379 TIR1 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 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
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003277 amino group Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000008335 axon cargo transport Effects 0.000 description 1
- 230000007844 axonal damage Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 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
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000003103 bodily secretion Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 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 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000006721 cell death pathway Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000045 chemical toxicity Toxicity 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 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 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 201000003636 hereditary ataxia Diseases 0.000 description 1
- 208000014188 hereditary optic neuropathy Diseases 0.000 description 1
- 201000006847 hereditary sensory neuropathy Diseases 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 102000048363 human NMRK1 Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000003230 hygroscopic agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- 229940042472 mineral oil Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 108010093470 monomethyl auristatin E Proteins 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000023105 myelination Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000013188 needle biopsy Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000020470 nervous system symptom Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 231100000878 neurological injury Toxicity 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 230000001561 neurotransmitter reuptake Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 201000005936 periventricular leukomalacia Diseases 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000004910 pleural fluid Anatomy 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- HAMAGKWXRRTWCJ-UHFFFAOYSA-N pyrido[2,3-b][1,4]oxazin-3-one Chemical compound C1=CN=C2OC(=O)C=NC2=C1 HAMAGKWXRRTWCJ-UHFFFAOYSA-N 0.000 description 1
- 230000006010 pyroptosis Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 230000008684 selective degradation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 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 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000003685 thermal hair damage Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 239000003440 toxic substance Substances 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
- 230000001052 transient effect Effects 0.000 description 1
- 201000006397 traumatic glaucoma Diseases 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
環Aが、それが縮合している炭素原子と一緒になって、6員アリール環、又は1~2個の窒素原子を有する6員ヘテロアリール環であり、
Xが、C-Rx及びNから選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個又は2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-、及び二価の3~5員の単環式、二環式、又は架橋二環式炭素環式環から独立して選択される基によって任意に置き換えられており、
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環から選択される任意に置換された基、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R2が、水素、ハロゲン、N(R′)2、OR′、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的不飽和、若しくはアリール炭素環式環、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和若しくは部分的に不飽和の複素環式環、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
R3が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rx及びRyが、水素、ハロゲン、シアノ、OR″、SR″、N(R″)2、及び任意に置換されたC1-4脂肪族から独立して選択され、
R、R′、及びR″の各々が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
R及びR2が、それらが結合している介在原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR′基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR″基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
nが、0、1、又は2である、化合物又はその薬学的に許容される塩を提供する。
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、5~6員のヘテロアリール環が、フッ素又はメチルで任意に置換され、
R2が、窒素及び硫黄から選択される1個のヘテロ原子を有する5~6員のヘテロアリール環、又はフェニルであり、5~6員ヘテロアリール環又はフェニルが、フッ素及び塩素から選択される1~2個の基で任意に置換され、
R4が、水素又はメチルであり、
Qが、N又はCHであり、
X、Y、及びZが、独立して、CR5又は窒素原子であるが、但し、2個以下のX、Y、及びZが、窒素原子であり、
R5が、水素又はメチルである、化合物又はその薬学的に許容される塩の構造を有する。
脂肪族:「脂肪族」という用語は、完全に飽和しているか、若しくは1つ以上の不飽和の単位を含有する、直鎖(すなわち、非分岐)若しくは分岐、置換若しくは非置換の炭化水素鎖、又は完全に飽和しているか、若しくは1つ以上の不飽和の単位を含有するが、芳香族ではなく(本明細書において「「炭化水素」又は「脂環式」」とも呼ばれる)、分子の残りの部分への単一の結合点を有する、単環式炭化水素又は二環式炭化水素を指す。特に明記しない限り、脂肪族基は、1~6個の脂肪族炭素原子を含有する。いくつかの実施形態において、脂肪族基は、1~5個の脂肪族炭素原子を含有する。他の実施形態において、脂肪族基は、1~4個の脂肪族炭素原子を含有する。さらに他の実施形態において、脂肪族基は、1~3個の脂肪族炭素原子を含有し、さらに他の実施形態において、脂肪族基は、1~2個の脂肪族炭素原子を含有する。いくつかの実施形態において、「脂環式」(又は「炭素環」)は、完全に飽和しているか、又は1つ以上の不飽和の単位を含有するが、芳香族ではない、単環式C3~C8炭化水素又は二環式C7~C10炭化水素を指す。好適な脂肪族基は、直鎖又は分岐鎖、置換又は非置換のアルキル、アルケニル、アルキニル、アルキレン、アルケニレン、アルキニレン基、及びそれらのハイブリッドが含まれるが、これらに限定されない。
プログラムされた軸索変性及びSARM1
軸索変性は、限定されないが、アルツハイマー病、パーキンソン病、ALS、多発性硬化症、糖尿病性末梢神経障害、化学療法誘発性末梢神経障害、遺伝性神経障害、外傷性脳損傷、及び/又は緑内障などの神経疾患の主要な病理学的特性である。損傷した軸索又は不健康な軸索は、ウォーラー変性として知られるアポトーシスのような従来の細胞死経路とは異なる固有の自己破壊プログラムによって排除される。(Gerdts,J.,et al.,Neuron,2016,89,449-460;Whitmore,A.V.et al.,Cell Death Differ.,2003,10,260-261)。ウォーラー変性の際、末梢神経は損傷の遠位にある軸索セグメントの選択的分解を受けるが、一方、近位軸索セグメント及び細胞体は無傷のままである。この変性は、最初にニコチンアミドモノヌクレオチドアデニルトランスフェラーゼ(NMNAT)の枯渇、続いてニコチンアミドアデニンジヌクレオチド(NAD+)の喪失、アデノシン三リン酸(ATP)の喪失、ニューロフィラメントタンパク質分解、及び損傷の約8~24時間後の軸索分解を特徴とする。(Gerdts,J.,et al.,Neuron,2016,89,449-460)。
いくつかの実施形態において、本開示は、式Iの化合物、
環Aが、それが縮合している炭素原子と一緒になって、6員アリール環、又は1~2個の窒素原子を有する6員ヘテロアリール環であり、
Xが、C-Rx及びNから選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個又は2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-、及び二価の3~5員の単環式、二環式、又は架橋二環式炭素環式環から独立して選択される基によって任意に置き換えられており、
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環から選択される任意に置換された基、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R2が、水素、ハロゲン、N(R′)2、OR′、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的不飽和、若しくはアリール炭素環式環、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和若しくは部分的に不飽和の複素環式環、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
R3が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rx及びRyが、水素、ハロゲン、シアノ、OR″、SR″、N(R″)2、及び任意に置換されたC1-4脂肪族から独立して選択され、
R、R′、及びR″の各々が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
R及びR2が、それらが結合している介在原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR′基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR″基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
nが、0、1、又は2である、化合物又はその薬学的に許容される塩を提供する。
-C(O)-によって置き換えられている。
-C(O)N(R)-によって置き換えられている。いくつかの実施形態において、Lは、
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、5~6員のヘテロアリール環が、フッ素又はメチルで任意に置換され、
R2が、窒素及び硫黄から選択される1個のヘテロ原子を有する5~6員のヘテロアリール環、又はフェニルであり、5~6員ヘテロアリール環又はフェニルが、フッ素及び塩素から選択される1~2個の基で任意に置換され、
R4が、水素又はメチルであり、
Qが、N又はCHであり、
X、Y、及びZが、独立して、CR5又は窒素原子であるが、但し、2個以下のX、Y、及びZが、窒素原子であり、
R5が、水素又はメチルである、化合物又はその薬学的に許容される塩の構造を有する。
環Aが、それが縮合している炭素原子と一緒になって、6員アリール環、又は1~2個の窒素原子を有する6員ヘテロアリール環であり、
Xが、C-Rx及びNから選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個又は2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-、及び二価の3~5員の単環式、二環式、又は架橋二環式炭素環式環から独立して選択される基によって任意に置き換えられており、
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環から選択される任意に置換された基、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R2が、水素、ハロゲン、N(R′)2、OR′、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的不飽和、若しくはアリール炭素環式環、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和若しくは部分的に不飽和の複素環式環、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
R3が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rx及びRyが、水素、ハロゲン、シアノ、OR″、SR″、N(R″)2、及び任意に置換されたC1-4脂肪族から独立して選択され、
R、R′、及びR″の各々が、独立して、水素、又はC1-6脂肪族から選択される任意に置換された基、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和若しくは部分的に不飽和の複素環式環、フェニル、並びに酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
R及びR2が、それらが結合している介在原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR′基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成するか、あるいは
2つのR″基が、それらが結合している窒素原子と一緒になって、酸素、窒素、及び硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
nが、0、1、又は2である、化合物又はその薬学的に許容される塩。
(i)軸索変性を特徴とする状態を有するか、又は(ii)軸索変性を特徴とする状態を発症するリスクがある対象に、実施形態1~99のいずれか1つに記載の化合物を投与するステップを含む、方法。
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、5~6員のヘテロアリール環が、フッ素又はメチルで任意に置換され、
R2が、窒素及び硫黄から選択される1個のヘテロ原子を有する5~6員のヘテロアリール環、又はフェニルであり、5~6員ヘテロアリール環又はフェニルが、フッ素及び塩素から選択される1~2個の基で任意に置換され、
R4が、水素又はメチルであり、
Qが、N又はCHであり、
X、Y、及びZが、独立して、CR5又は窒素原子であるが、但し、2個以下のX、Y、及びZが、窒素原子であり、
R5が、水素又はメチルである、化合物又はその薬学的に許容される塩。
いくつかの実施形態において、式I/IIの化合物は、組成物において、例えば、1つ以上の他の成分との組み合わせ(例えば、混合物)で提供され得る。
とりわけ、本開示は、本明細書に記載される化合物及び/又は組成物の同定及び/又は特性評価のための様々な技術を提供する。例えば、本開示は、SARM1阻害活性を評価するための、特に、SARM1阻害活性を評価するための様々なアッセイを提供する。
いくつかの実施形態において、SARM1阻害剤を同定する方法は、a)i)SARM1の変異体又はフラグメント、ii)NAD+、及びiii)候補阻害剤を含む混合物を提供することであって、変異体又はフラグメントは、構成的活性を有する、提供することと、b)混合物をインキュベートすることと、c)インキュベーション後の混合物中のNAD+を定量化することと、d)NAD+の量が、候補阻害剤を含有しない対照混合物の量よりも多い場合、候補阻害剤化合物を阻害剤として同定することと、を含む。
いくつかの実施形態において、提供されるSARM1阻害剤の有効性は、例えば、2018年3月29日に公開されたWO2018/057989に記載されたアッセイに従って決定することができ、参照によりその全体が本明細書に組み込まれる。いくつかの実施形態において、提供されるSARM1阻害剤は、SARM1又はそのフラグメントを含有する溶液に適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、インビトロシステムに適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、インビボで適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、患者に適用することができる。いくつかの実施形態において、SARM1阻害剤は、エピトープタグで標識されたSARM1又はそのフラグメントと混合することができる。いくつかの実施形態において、結合されたSARM1阻害剤の量は、結合されていないSARM1阻害剤の量と比較され得、SARM1阻害剤に対する親和性をもたらす。
いくつかの実施形態において、SARM1-TIRドメインは、例えば、精製において有用であり得る様々なタンパク質又はエピトープ、タグで操作することができる。いくつかの実施形態において、本開示はまた、ニコチンアミドリボシドキナーゼ1(NRK1)で形質転換されたHEK293T細胞を含むNRK1-HEK293T細胞株を提供する。いくつかの実施形態において、HEK293T細胞は、ニコチンアミドリボシドキナーゼ1(NRK1)をコードするDNA配列で形質転換又はトランスフェクトされた。いくつかの実施形態において、NRK1をコードするDNAは、ゲノム又はcDNAであり得る。いくつかの実施形態において、HEK293T細胞は、宿主細胞に対して外因性の供給源からNRK1をコードするDNAで安定的又は一時的にトランスフェクトされる。いくつかの実施形態において、HEK293T細胞は、細胞が対照細胞と比較して高いレベルでNRK1を発現するように、NRK1をコードするDNAで安定的又は一時的にトランスフェクトされる。いくつかの実施形態において、NRK1をコードするDNAは、プロモーター、エンハンサー、又はそれらの組み合わせなどの1つ以上の外因性調節DNA配列の制御下にある。いくつかの実施形態において、NRK1をコードするDNA配列と調節配列との組み合わせは、天然に存在しない組み合わせである。いくつかの実施形態において、NRK1をコードするDNAは、ゲノム又はcDNAのいずれかであり、FCIV発現ベクターなどの発現ベクターを含む。いくつかの実施形態において、NRK1をコードするDNAは、脊椎動物又は無脊椎動物種、例えば、これらに限定されないが、ヒト、マウス、ゼブラフィッシュ、又はショウジョウバエからのゲノムDNA又はcDNAに由来する。いくつかの構成において、NRK1 DNAは、ヒトNRK1 DNAである。
本開示は、例えば、本明細書に記載されるそれらの活性及び/又は特徴の見地から、本明細書に記載される化合物及び/又は組成物の様々な使用及び用途を提供する。いくつかの実施形態において、そのような使用は、治療的及び/又は診断的使用を含み得る。代替的に、いくつかの実施形態において、そのような使用は、研究、生産、及び/又は他の技術的使用を含み得る。
いくつかの実施形態において、本明細書に記載される化合物及び/又は組成物は、1つ以上の疾患、障害、又は状態に罹患している対象に投与することができる。いくつかの実施形態において、1つ以上の疾患、障害、又は状態は、SARM1によって媒介される。
いくつかの実施形態において、本明細書に記載される化合物及び/又は組成物は、本明細書に記載の疾患、障害若しくは状態に罹患している、又は罹患しやすい対象に投与される。いくつかの実施形態において、そのような疾患、障害、又は状態は、本明細書で言及される状態の1つなどの軸索変性を特徴とする。
当業者は、いくつかの実施形態において、本明細書に記載されるような薬学的組成物若しくはレジメンの投与に含まれる及び/又は投与によって送達される特定の化合物の正確な量が、医師によって選択され得、例えば、対象の1つ以上の種、年齢、及び一般的な状態、及び/又は特定の化合物若しくは組成物の同一性、その投与方法などを考慮して、異なる対象に対して異なっていてもよいことを理解するであろう。代替的に、いくつかの実施形態において、本明細書に記載されるような薬学的組成物又はレジメンの投与に含まれる及び/又は投与される特定の化合物の量は、関連する患者集団(例えば、すべての患者、特定の年齢若しくは疾患のすべての患者、又は特定のバイオマーカーを発現しているすべての患者など)にわたって標準化され得る。
本明細書に記載のいくつかの方法及び組成物は、当業者に周知の実験技術を利用し、Sambrook,J.,et al.,Molecular Cloning:A Laboratory Manual,3rd ed.Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,2001、Methods In Molecular Biology,ed.Richard,Humana Press,NJ,1995、Spector,D.L.et al.,Cells:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1998、及びHarlow,E.,Using Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1999などの実験マニュアルに認めることができる。医薬品の投与方法及び投与レジメンは、Remington:the Science and Practice of Pharmacy(Alfonso R.Gennaro ed.19th ed.1995)、Hardman,J.G.,et al.,Goodman & Gilman’s The Pharmacological Basis of Therapeutics,Ninth Edition,McGraw-Hill,1996、及びRowe,R.C.,et al.,Handbook of Pharmaceutical Excipients,Fourth Edition,Pharmaceutical Press,2003などの標準的な参照テキストによって提供される方法を使用して、薬理学の標準的な原則に従って決定することができる。
一般的な合成方法
本発明による化合物及びそれらの中間体は、当業者に知られており、有機合成の文献に記載されている合成方法を使用して得られ得る。好ましくは、化合物は、特に実験のセクションに記載されるように、以下により完全に説明される調製方法に類似した方法で得られる。場合によっては、反応ステップを実行する順序は、変更され得る。当業者には知られているが、ここでは詳細に説明されていない反応方法の変種も使用され得る。
a)Waters Xbridge C18 10μm 30×100mmカラム
b)Waters Sunfire C18 10μm 30×100mmカラム
c)Waters Xbridge C18 3.5μm 50×4.6mmカラム
d)HALO C18 2.7μm 30×4.6mmカラム
e)Waters Sunfire C18 3.5μm 50×4.6mmカラム
インダゾール、アザインダゾール、及びインドール中間体の合成
方法A:中間体I-1の合成
方法G:実施例16の合成
LCMS方法:
分析LC/MS分析方法A:
ESI+/-イオンモード150-850Da
カラム:Phenomenex Kinetix-XB C18、品番00D-4498-AN、2.1×100mm、1.7μm
温度:40℃
勾配:
ESI+/-イオンモード150-850Da
カラム:Phenomenex Gemini-NX C18、品番00D-4453-B0、2.0×100mm、3.0μm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Waters UPLC(登録商標)BEH(商標)C18、品番186002352、2.1×100mm。1.7μm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:XBridge C18、3.5μm 4.6×50mm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:XBridge SB-C18、3.5μm 4.6×50mm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Sunfire C18、3.5μm 4.6×50mm
温度:50℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Waters UPLC(登録商標)BEH(商標)C18、品番186005297、1.7μm 2.1×50mm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Sunfire C18、3.5μm 4.6×50mm
温度:50℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:XBridge C18、3.5μm 4.6×50mm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:XBridge C18、3.5μm 4.6×50mm
温度:45℃
勾配:
この実施例は、ARM-SAM-TIR NADアーゼ活性のアッセイ、及びSARM1媒介NAD+切断をブロックするための式I/IIの化合物の有効性を測定するためのこのアッセイの使用を説明する。このアッセイは、SARM1活性を阻害する式I/IIの化合物の有効性を特徴付け、各化合物のIC50値を計算するように最適化されている。このアッセイは、ARM、SAM、及びTIRドメインを含む全長のSARM1を使用する。本明細書に示されるように、自己阻害性N-末端ドメインなしでのこのフラグメントの発現は、NAD+を切断する構成的に活性な酵素を生成する。
NRK1-HEK293T細胞を、150cm2のプレート上に20×106細胞/プレートで播種した。翌日、細胞を15μgのARM-SAM-TIR発現プラスミド、配列番号1でトランスフェクトした。
GCGATCGCGGCTCCCGACATCTTGGACCATTAGCTCCACAGGTATCTTCTTCCCTCTAGTGGTCATAACAGCAGCTTCAG
CTACCTCTCAATTCAAAAAACCCCTCAAGACCCGTTTAGAGGCCCCAAGGGGTTATGCTATCAATCGTTGCGTTACACAC
ACAAAAAACCAACACACATCCATCTTCGATGGATAGCGATTTTATTATCTAACTGCTGATCGAGTGTAGCCAGATCTAGT
AATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGC
TGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTG
ACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTA
TTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTAC
ATCTACGTATTAGTCATCGCTATTACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTC
ACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAAT
GTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTA
GTGAACCGTCAGATCAGATCTTTGTCGATCCTACCATCCACTCGACACACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGC
TCTCGAATTCAAAGGAGGTACCCACcatgGCCATGCATCACCACCACCATCATAGCTCCGGCGTCGACCTCGGCACCGAG
AATTTATATTTCCAAAGCGGCCTCAATGATATCTTCGAGGCCCAGAAGATCGAGTGGCACGAGGGCAGCTCCGACCTCGC
CGTGCCCGGTCCCGATGGAGGCGGAGGCACTGGTCCTTGGTGGGCTGCTGGCGGCAGAGGCCCTAGAGAAGTGAGCCCCG
GTGCTGGCACCGAGGTGCAAGACGCTCTGGAGAGGGCTCTGCCCGAACTGCAGCAAGCTCTGTCCGCTTTAAAGCAAGCT
GGAGGAGCTAGAGCCGTCGGCGCCGGACTGGCCGAAGTGTTCCAGCTCGTGGAGGAAGCTTGGTTATTACCCGCTGTGGG
AAGAGAGGTCGCCCAAGGTCTGTGTGACGCCATTCGTCTGGACGGAGGTTTAGACTTATTACTGAGGCTGCTGCAAGCTC
CCGAACTGGAGACAAGGGTCCAAGCTGCTCGTCTGCTGGAGCAGATCCTCGTGGCCGAGAATCGTGACAGAGTGGCTAGA
ATCGGTTTAGGCGTCATCCTCAATTTAGCCAAAGAGAGGGAGCCCGTTGAGCTGGCCAGAAGCGTCGCTGGCATCCTCGA
GCACATGTTCAAGCATTCCGAGGAGACTTGTCAGAGACTGGTCGCCGCCGGAGGACTCGATGCTGTTTTATACTGGTGCA
GAAGGACAGACCCCGCTTTACTGAGGCATTGTGCTCTGGCCCTCGGCAATTGCGCTTTACATGGAGGCCAAGCCGTCCAG
AGAAGGATGGTGGAGAAAAGAGCCGCCGAGTGGCTGTTCCCTTTAGCCTTCTCCAAAGAAGACGAACTGTTACGTCTGCA
TGCTTGTCTCGCTGTCGCTGTTTTAGCCACCAACAAGGAGGTGGAAAGGGAAGTGGAAAGAAGCGGAACACTGGCTTTAG
TCGAACCTCTGGTGGCTTCTTTAGATCCCGGAAGGTTTGCCAGATGTCTGGTCGACGCCAGCGATACCTCCCAAGGAAGA
GGCCCCGACGATCTCCAGAGACTGGTGCCTCTGCTGGACAGCAATCGTCTGGAGGCCCAATGTATTGGCGCCTTCTATCT
CTGCGCCGAAGCCGCCATCAAGTCTTTACAAGGTAAGACCAAGGTGTTCTCCGACATTGGAGCCATCCAATCTTTAAAGA
GGCTGGTGAGCTATTCCACCAACGGCACAAAAAGCGCTTTAGCCAAAAGAGCTTTAAGACTGCTGGGCGAAGAGGTGCCT
AGGCCCATTTTACCTTCCGTGCCTAGCTGGAAGGAGGCCGAGGTGCAGACTTGGCTGCAGCAGATCGGCTTTAGCAAATA
TTGCGAATCCTTTAGGGAGCAGCAAGTTGACGGCGATTTATTATTAAGGCTGACCGAGGAAGAGCTCCAGACAGATTTAG
GCATGAAAAGCGGCATCACTCGTAAGAGGTTCTTTCGTGAGCTCACCGAACTGAAGACCTTCGCCAACTACTCCACTTGT
GATCGTAGCAATTTAGCTGATTGGCTCGGATCCCTCGATCCCAGATTTCGTCAGTACACCTATGGACTCGTCTCTTGTGG
ACTGGACAGATCTTTACTGCATCGTGTGAGCGAGCAACAGCTGCTGGAAGATTGCGGCATCCATTTAGGAGTGCACAGAG
CCAGAATTCTGACCGCCGCTAGAGAGATGCTGCATTCCCCTCTCCCTTGTACCGGAGGCAAGCCTAGCGGAGACACCCCC
GACGTGTTCATCAGCTATCGTAGAAACAGCGGAAGCCAGCTGGCCTCTTTACTGAAGGTCCATTTACAGCTGCACGGATT
TAGCGTCTTCATCGACGTGGAGAAACTGGAGGCTGGCAAGTTCGAGGACAAGCTGATCCAGTCCGTGATGGGCGCTAGGA
ATTTCGTTTTAGTGCTCAGCCCCGGCGCTCTGGATAAATGCATGCAAGATCATGACTGTAAGGACTGGGTCCACAAGGAA
ATCGTGACCGCTCTGTCTTGTGGCAAGAACATCGTCCCCATCATCGACGGCTTCGAATGGCCCGAGCCTCAAGTTCTCCC
CGAAGATATGCAAGCTGTTTTAACCTTCAATGGAATCAAGTGGAGCCACGAGTACCAAGAAGCCACAATCGAGAAGATCA
TTCGTTTTCTGCAAGGTAGATCCTCCAGAGATTCCTCCGCTGGCAGCGACACATCTTTAGAGGGCGCCGCCCCTATGGGT
CCTACCTAATAATctagAAGTTGTCTCCTCCTGCACTGACTGACTGATACAATCGATTTCTGGATCCGCAGGCCTCTGCT
AGCTTGACTGACTGAGATACAGCGTACCTTCAGCTCACAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAAC
TAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATA
AACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAA
AACCTCTACAAATGTGGTATTGGCCCATCTCTATCGGTATCGTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGG
GGTTTTTTGTGCCCCTCGGGCCGGATTGCTATCTACCGGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTC
TTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCA
GAAATTTATCCTTAAGGTCGTCAGCTATCCTGCAGGCGATCTCTCGATTTCGATCAAGACATTCCTTTAATGGTCTTTTC
TGGACACCACTAGGGGTCAGAAGTAGTTCATCAAACTTTCTTCCCTCCCTAATCTCATTGGTTACCTTGGGCTATCGAAA
CTTAATTAACCAGTCAAGTCAGCTACTTGGCGAGATCGACTTGTCTGGGTTTCGACTACGCTCAGAATTGCGTCAGTCAA
GTTCGATCTGGTCCTTGCTATTGCACCCGTTCTCCGATTACGAGTTTCATTTAAATCATGTGAGCAAAAGGCCAGCAAAA
GGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGAC
GCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCT
CCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACG
CTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCT
GCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAAC
AGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAAC
AGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCA
CCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATC
TTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTT
CACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACC
AATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCATTTAAATTTCCGAACTCT
CCAAGGCCCTCGTCGGAAAATCTTCAAACCTTTCGTCCGATCCATCTTGCAGGCTACCTCTCGAACGAACTATCGCAAGT
CTCTTGGCCGGCCTTGCGCCTTGGCTATTGCTTGGCAGCGCCTATCGCCAGGTATTACTCCAATCCCGAATATCCGAGAT
CGGGATCACCCGAGAGAAGTTCAACCTACATCCTCAATCCCGATCTATCCGAGATCCGAGGAATATCGAAATCGGGGCGC
GCCTGGTGTACCGAGAACGATCCTCTCAGTGCGAGTCTCGACGATCCATATCGTTGCTTGGCAGTCAGCCAGTCGGAATC
CAGCTTGGGACCCAGGAAGTCCAATCGTCAGATATTGTACTCAAGCCTGGTCACGGCAGCGTACCGATCTGTTTAAACCT
AGATATTGATAGTCTGATCGGTCAACGTATAATCGAGTCCTAGCTTTTGCAAACATCTATCAAGAGACAGGATCAGCAGG
AGGCTTTCGCATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTC
ACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCGCGAGTGGGTTACATCGAACTGGATCTCAAC
AGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGCTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGC
GGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTATT
CACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAAC
ACTGCGGCCAACTTACTTCTGACAACGATTGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGT
AACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAA
TGGCAACAACCTTGCGTAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAGTTGATAGACTGGATGGAG
GCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGA
GCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGA
GTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACCGATTCTA
GGTGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGAT
ACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGATCCCGAATCGTTTAAACT
CGACTCTGGCTCTATCGAATCTCCGTCGTTTCGAGCTTACGCGAACAGCCGTGGCGCTCATTTGCTCGTCGGGCATCGAA
TCTCGTCAGCTATCGTCAGCTTACCTTTTTGGCA(配列番号1)。
酵素アッセイは、DulbeccoのPBS緩衝液中の384ウェルポリプロピレンプレートで、20μLの最終アッセイ容量で実施した。最終濃度5μg/mLのARM-SAM-TIR溶解物を、室温で2時間にわたって1%DMSO最終アッセイ濃度でそれぞれの化合物とプレインキュベートした。基質として5μMの最終アッセイ濃度のNAD+を添加することにより反応を開始した。2時間の室温インキュベーション後、アセトニトリル中の7.5%トリクロロ酢酸の停止溶液40μLで反応を停止させた。NAD+及びADPR濃度は、API4000トリプル四重極質量分析計(AB Sciex Framingham、MA)を使用して、RapidFire高スループット質量分析システム(Agilent Technologies、Santa Clara,CA)によって分析された。
この実施例は、式I/IIの化合物を特徴付けるために使用されるインビトロ軸索変性アッセイを示す。このアッセイを使用して、マウス後根神経節(DRG)点滴培養における軸索変性を予防するための式I/IIの化合物の有効性を試験した。
Claims (6)
- 下式の化合物:
又はその薬学的に許容される塩であって、式中、
R1が、酸素、窒素、及び硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、前記5~6員のヘテロアリール環が、フッ素又はメチルで置換されていてもよく、
R2が、窒素及び硫黄から選択される1個のヘテロ原子を有する5~6員のヘテロアリール環、又はフェニルであり、前記5~6員ヘテロアリール環又はフェニルが、フッ素及び塩素から選択される1~2個の基で置換されていてもよく、
R4が、水素又はメチルであり、
Qが、Nであり、
X、Y、及びZが、独立して、CR5又は窒素原子であるが、但し、2個以下のX、Y、及びZが、窒素原子であり、
R5が、水素又はメチルである、化合物又はその薬学的に許容される塩。 -
又はその薬学的に許容される塩から選択される、請求項1に記載の化合物。 - 請求項1又は請求項2のいずれかに記載の化合物と、薬学的に許容される担体とを含む、薬学的組成物。
- (i)軸索変性を特徴とする状態、又は(ii)軸索変性を特徴とする状態を発症するリスクを低減するのに用いられる、請求項1又は請求項2のいずれかに記載の化合物を含む、薬学的組成物。
- 軸索変性を治療又は予防するための、請求項1又は請求項2のいずれかに記載の化合物を含む、薬学的組成物。
- SARM1を阻害する方法であって、生物学的試料を請求項1又は請求項2のいずれかに記載の化合物と接触させることを含む、方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063007773P | 2020-04-09 | 2020-04-09 | |
US63/007,773 | 2020-04-09 | ||
PCT/US2021/026102 WO2021207302A1 (en) | 2020-04-09 | 2021-04-07 | Indazole derivatives as inhibitors of sarm1 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2023520923A JP2023520923A (ja) | 2023-05-22 |
JP7478252B2 true JP7478252B2 (ja) | 2024-05-02 |
Family
ID=75690685
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022561466A Active JP7478252B2 (ja) | 2020-04-09 | 2021-04-07 | Sarm1の阻害剤 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230286978A1 (ja) |
EP (1) | EP4132920A1 (ja) |
JP (1) | JP7478252B2 (ja) |
CN (1) | CN115916764A (ja) |
CA (1) | CA3174321A1 (ja) |
WO (1) | WO2021207302A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022031736A1 (en) * | 2020-08-04 | 2022-02-10 | Nura Bio, Inc. | Substituted pyridine derivatives as sarm1 inhibitors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019236879A1 (en) | 2018-06-07 | 2019-12-12 | Disarm Therapeutics, Inc. | Inhibitors of sarm1 |
JP2019535804A (ja) | 2016-09-24 | 2019-12-12 | ワシントン・ユニバーシティWashington University | Sarm1 nadアーゼ活性の阻害剤およびその使用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101247853B (zh) * | 2005-04-13 | 2014-11-12 | 轴突公司 | 具有nos抑制活性的取代的吲哚化合物 |
EP2647634A1 (en) * | 2012-04-02 | 2013-10-09 | Noscira, S.A. | Indole-pyrimidine derivatives and their therapeutic uses |
KR20150000900A (ko) * | 2012-04-10 | 2015-01-05 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | 신규한 1-치환된 인다졸 유도체 |
WO2015121812A1 (en) * | 2014-02-12 | 2015-08-20 | Iteos Therapeutics | Novel 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use |
AU2018209667B2 (en) * | 2017-01-17 | 2020-05-07 | Astrazeneca Ab | JAK1 selective inhibitors |
KR102195348B1 (ko) * | 2018-11-15 | 2020-12-24 | 에이치케이이노엔 주식회사 | 단백질 키나제 억제제로서의 신규 화합물 및 이를 포함하는 약제학적 조성물 |
BR112022000325A2 (pt) * | 2019-07-11 | 2022-03-15 | Escape Bio Inc | Indazois e azaindazois como inibidores de lrrk2 |
-
2021
- 2021-04-07 CA CA3174321A patent/CA3174321A1/en active Pending
- 2021-04-07 US US17/995,046 patent/US20230286978A1/en active Pending
- 2021-04-07 EP EP21722042.5A patent/EP4132920A1/en active Pending
- 2021-04-07 JP JP2022561466A patent/JP7478252B2/ja active Active
- 2021-04-07 WO PCT/US2021/026102 patent/WO2021207302A1/en unknown
- 2021-04-07 CN CN202180041975.7A patent/CN115916764A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019535804A (ja) | 2016-09-24 | 2019-12-12 | ワシントン・ユニバーシティWashington University | Sarm1 nadアーゼ活性の阻害剤およびその使用 |
WO2019236879A1 (en) | 2018-06-07 | 2019-12-12 | Disarm Therapeutics, Inc. | Inhibitors of sarm1 |
Also Published As
Publication number | Publication date |
---|---|
EP4132920A1 (en) | 2023-02-15 |
WO2021207302A1 (en) | 2021-10-14 |
JP2023520923A (ja) | 2023-05-22 |
CA3174321A1 (en) | 2021-10-14 |
US20230286978A1 (en) | 2023-09-14 |
CN115916764A (zh) | 2023-04-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7319395B2 (ja) | Sarm1の阻害剤 | |
JP7289375B2 (ja) | Sarm1の阻害剤 | |
AU2021206651B2 (en) | Inhibitors of SARM1 | |
AU2021333558B2 (en) | Inhibitors of SARM1 | |
JP2024037770A (ja) | Sarm1阻害剤 | |
JP7478142B2 (ja) | Sarm1阻害剤 | |
JP7478252B2 (ja) | Sarm1の阻害剤 | |
US20240051939A1 (en) | Benzopyrazole inhibitors of sarm1 | |
JP7477642B2 (ja) | Sarm1の阻害剤 | |
US20220315568A1 (en) | Inhibitors of sarm1 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221206 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20221206 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20231109 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231205 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240209 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240409 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240419 |