JP6250394B2 - 軽度の認知障害(mci)および関連障害の処置方法 - Google Patents
軽度の認知障害(mci)および関連障害の処置方法 Download PDFInfo
- Publication number
- JP6250394B2 JP6250394B2 JP2013525003A JP2013525003A JP6250394B2 JP 6250394 B2 JP6250394 B2 JP 6250394B2 JP 2013525003 A JP2013525003 A JP 2013525003A JP 2013525003 A JP2013525003 A JP 2013525003A JP 6250394 B2 JP6250394 B2 JP 6250394B2
- Authority
- JP
- Japan
- Prior art keywords
- disease
- administration
- compound
- app
- alzheimer
- 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
- 208000010877 cognitive disease Diseases 0.000 title claims description 100
- 208000027061 mild cognitive impairment Diseases 0.000 title claims description 93
- 238000000034 method Methods 0.000 title claims description 85
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 62
- 208000024827 Alzheimer disease Diseases 0.000 claims description 136
- 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 claims description 87
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 claims description 84
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 claims description 84
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 claims description 83
- 229960003688 tropisetron Drugs 0.000 claims description 63
- 241000124008 Mammalia Species 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 50
- 208000024891 symptom Diseases 0.000 claims description 31
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 28
- 230000009467 reduction Effects 0.000 claims description 26
- 238000012545 processing Methods 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 108010048112 Amyloidogenic Proteins Proteins 0.000 claims description 13
- 102000009091 Amyloidogenic Proteins Human genes 0.000 claims description 13
- 230000003942 amyloidogenic effect Effects 0.000 claims description 13
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 claims description 12
- 208000015756 familial Alzheimer disease Diseases 0.000 claims description 12
- 230000007450 amyloidogenic pathway Effects 0.000 claims description 11
- 230000035772 mutation Effects 0.000 claims description 11
- 230000001737 promoting effect Effects 0.000 claims description 7
- 108700028369 Alleles Proteins 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 4
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 claims 4
- 150000003840 hydrochlorides Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 163
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 119
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 72
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 72
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 65
- 229960002563 disulfiram Drugs 0.000 description 57
- 201000010099 disease Diseases 0.000 description 55
- 238000011282 treatment Methods 0.000 description 53
- GWUSZQUVEVMBPI-UHFFFAOYSA-N nimetazepam Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1 GWUSZQUVEVMBPI-UHFFFAOYSA-N 0.000 description 52
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 description 51
- 229950001981 nimetazepam Drugs 0.000 description 51
- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 description 50
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 description 49
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 47
- 210000004556 brain Anatomy 0.000 description 47
- 239000000203 mixture Substances 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 35
- 230000000694 effects Effects 0.000 description 35
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 33
- 238000003776 cleavage reaction Methods 0.000 description 31
- 230000007017 scission Effects 0.000 description 31
- 108010026424 tau Proteins Proteins 0.000 description 29
- 102000013498 tau Proteins Human genes 0.000 description 29
- 206010012289 Dementia Diseases 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 238000003556 assay Methods 0.000 description 24
- 239000000758 substrate Substances 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 20
- 108090000765 processed proteins & peptides Proteins 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 16
- 239000013543 active substance Substances 0.000 description 16
- 230000003941 amyloidogenesis Effects 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 15
- 239000000090 biomarker Substances 0.000 description 15
- 230000001965 increasing effect Effects 0.000 description 15
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 208000037259 Amyloid Plaque Diseases 0.000 description 13
- 238000007918 intramuscular administration Methods 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 210000002381 plasma Anatomy 0.000 description 12
- 230000002265 prevention Effects 0.000 description 12
- 230000003930 cognitive ability Effects 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 238000001990 intravenous administration Methods 0.000 description 11
- 210000005171 mammalian brain Anatomy 0.000 description 11
- 238000007920 subcutaneous administration Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000012634 fragment Substances 0.000 description 10
- 230000007170 pathology Effects 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- -1 tropisetron (Navo) Chemical class 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000000544 cholinesterase inhibitor Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 210000001353 entorhinal cortex Anatomy 0.000 description 9
- 230000002068 genetic effect Effects 0.000 description 9
- 210000001320 hippocampus Anatomy 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 230000007505 plaque formation Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 208000012902 Nervous system disease Diseases 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 238000012636 positron electron tomography Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 230000037317 transdermal delivery Effects 0.000 description 7
- 230000009261 transgenic effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 6
- 239000000443 aerosol Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000006999 cognitive decline Effects 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 201000000980 schizophrenia Diseases 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 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 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000001149 cognitive effect Effects 0.000 description 5
- 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 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000001537 neural effect Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 229960003674 tropisetron hydrochloride Drugs 0.000 description 5
- 238000010173 Alzheimer-disease mouse model Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000026139 Memory disease Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- PBHFNBQPZCRWQP-QUCCMNQESA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n-phenylcarbamate Chemical compound CN([C@@H]1[C@@](C2=C3)(C)CCN1C)C2=CC=C3OC(=O)NC1=CC=CC=C1 PBHFNBQPZCRWQP-QUCCMNQESA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 230000002354 daily effect Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000002595 magnetic resonance imaging Methods 0.000 description 4
- 206010027175 memory impairment Diseases 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- CTPKSRZFJSJGML-UHFFFAOYSA-N sulfiram Chemical compound CCN(CC)C(=S)SC(=S)N(CC)CC CTPKSRZFJSJGML-UHFFFAOYSA-N 0.000 description 4
- 229950008316 sulfiram Drugs 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- YLUSMKAJIQOXPV-UHFFFAOYSA-N 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-amine Chemical compound C1CCCC2=C1N=C1CCCC1=C2N YLUSMKAJIQOXPV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 3
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- ZRJBHWIHUMBLCN-SEQYCRGISA-N Huperzine A Natural products N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- RVOLLAQWKVFTGE-UHFFFAOYSA-N Pyridostigmine Chemical compound CN(C)C(=O)OC1=CC=C[N+](C)=C1 RVOLLAQWKVFTGE-UHFFFAOYSA-N 0.000 description 3
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 3
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- OMHBPUNFVFNHJK-UHFFFAOYSA-P ambenonium Chemical compound C=1C=CC=C(Cl)C=1C[N+](CC)(CC)CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl OMHBPUNFVFNHJK-UHFFFAOYSA-P 0.000 description 3
- 229960000451 ambenonium Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000006933 amyloid-beta aggregation Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000007131 anti Alzheimer effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- MTCMTKNMZCPKLX-UHFFFAOYSA-N chembl359570 Chemical compound N=1OC=2C=C3NC(=O)CC3=CC=2C=1CCC(CC1)CCN1CC1=CC=CC=C1 MTCMTKNMZCPKLX-UHFFFAOYSA-N 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
- 230000001934 delay Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 229960003530 donepezil Drugs 0.000 description 3
- 210000002257 embryonic structure Anatomy 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 229960003980 galantamine Drugs 0.000 description 3
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 3
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 3
- 229950010480 icopezil Drugs 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229960005490 ipidacrine Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 210000003097 mucus Anatomy 0.000 description 3
- 229960002362 neostigmine Drugs 0.000 description 3
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 3
- 230000000508 neurotrophic effect Effects 0.000 description 3
- 210000002475 olfactory pathway Anatomy 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 3
- 229960001697 physostigmine Drugs 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229960002290 pyridostigmine Drugs 0.000 description 3
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 229960004136 rivastigmine Drugs 0.000 description 3
- CDAISMWEOUEBRE-CDRYSYESSA-N scyllo-inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O CDAISMWEOUEBRE-CDRYSYESSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 229960001685 tacrine Drugs 0.000 description 3
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- PMBLXLOXUGVTGB-UHFFFAOYSA-N zanapezil Chemical compound C=1C=C2CCCCNC2=CC=1C(=O)CCC(CC1)CCN1CC1=CC=CC=C1 PMBLXLOXUGVTGB-UHFFFAOYSA-N 0.000 description 3
- 229950010696 zanapezil Drugs 0.000 description 3
- PHOZOHFUXHPOCK-QMMMGPOBSA-N (2s)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)[C@H](CC)SC11CCN(C)CC1 PHOZOHFUXHPOCK-QMMMGPOBSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- JVJUWEFOGFCHKR-UHFFFAOYSA-N 2-(diethylamino)ethyl 1-(3,4-dimethylphenyl)cyclopentane-1-carboxylate;hydrochloride Chemical compound Cl.C=1C=C(C)C(C)=CC=1C1(C(=O)OCCN(CC)CC)CCCC1 JVJUWEFOGFCHKR-UHFFFAOYSA-N 0.000 description 2
- ZQAQXZBSGZUUNL-BJUDXGSMSA-N 2-[4-(methylamino)phenyl]-1,3-benzothiazol-6-ol Chemical compound C1=CC(N[11CH3])=CC=C1C1=NC2=CC=C(O)C=C2S1 ZQAQXZBSGZUUNL-BJUDXGSMSA-N 0.000 description 2
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WRDABNWSWOHGMS-UHFFFAOYSA-N AEBSF hydrochloride Chemical compound Cl.NCCC1=CC=C(S(F)(=O)=O)C=C1 WRDABNWSWOHGMS-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000000044 Amnesia 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
- 208000034048 Asymptomatic disease Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 102000016550 Complement Factor H Human genes 0.000 description 2
- 108010053085 Complement Factor H Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 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
- 206010061818 Disease progression Diseases 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 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 2
- 241000699660 Mus musculus Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010050254 Presenilins Proteins 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical compound SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 238000000333 X-ray scattering Methods 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000013024 dilution buffer Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 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
- 230000007246 mechanism Effects 0.000 description 2
- 230000006984 memory degeneration Effects 0.000 description 2
- 208000023060 memory loss Diseases 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 230000006996 mental state Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000031864 metaphase Effects 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000002159 nanocrystal Substances 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 239000006201 parenteral dosage form Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- ZSTLCHCDLIUXJE-ZGBAEQJLSA-N (2S,5S)-2-methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane] hydrate dihydrochloride Chemical compound O.Cl.Cl.C1S[C@@H](C)O[C@@]21C(CC1)CCN1C2.C1S[C@@H](C)O[C@@]21C(CC1)CCN1C2 ZSTLCHCDLIUXJE-ZGBAEQJLSA-N 0.000 description 1
- VFCRKLWBYMDAED-REWPJTCUSA-N (2s)-2-[[(2s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino]-n-[1-[1-(2,2-dimethylpropylamino)-2-methylpropan-2-yl]imidazol-4-yl]pentanamide Chemical compound O=C([C@@H](N[C@@H]1CC2=C(F)C=C(F)C=C2CC1)CCC)NC1=CN(C(C)(C)CNCC(C)(C)C)C=N1 VFCRKLWBYMDAED-REWPJTCUSA-N 0.000 description 1
- PUOAETJYKQITMO-LANLRWRYSA-N (3e)-1-[(1s)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1([C@H](C)N2CCC\C(C2=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC=C(F)C=C1 PUOAETJYKQITMO-LANLRWRYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- XCGJIFAKUZNNOR-UHFFFAOYSA-N 3-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid Chemical compound C1CC(CCC(=O)O)CCC1(S(=O)(=O)C=1C=CC(Cl)=CC=1)C1=CC(F)=CC=C1F XCGJIFAKUZNNOR-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- PSXOKXJMVRSARX-SCSAIBSYSA-N 5-chloro-n-[(2s)-4,4,4-trifluoro-1-hydroxy-3-(trifluoromethyl)butan-2-yl]thiophene-2-sulfonamide Chemical compound FC(F)(F)C(C(F)(F)F)[C@@H](CO)NS(=O)(=O)C1=CC=C(Cl)S1 PSXOKXJMVRSARX-SCSAIBSYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108010060159 Apolipoprotein E4 Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- XEAOPVUAMONVLA-QGZVFWFLSA-N Avagacestat Chemical compound C=1C=C(Cl)C=CC=1S(=O)(=O)N([C@H](CCC(F)(F)F)C(=O)N)CC(C(=C1)F)=CC=C1C=1N=CON=1 XEAOPVUAMONVLA-QGZVFWFLSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 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
- DSCFFEYYQKSRSV-KLJZZCKASA-N D-pinitol Chemical compound CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]1O DSCFFEYYQKSRSV-KLJZZCKASA-N 0.000 description 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- VWLHWLSRQJQWRG-UHFFFAOYSA-O Edrophonum Chemical compound CC[N+](C)(C)C1=CC=CC(O)=C1 VWLHWLSRQJQWRG-UHFFFAOYSA-O 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100500493 Mus musculus Eapp gene Proteins 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 108010063605 Netrins Proteins 0.000 description 1
- 102000010803 Netrins Human genes 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000017488 activation-induced cell death of T cell Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 101150031224 app gene Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 208000013404 behavioral symptom Diseases 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- OATNQHYJXLHTEW-UHFFFAOYSA-N benzene-1,4-disulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(S(O)(=O)=O)C=C1 OATNQHYJXLHTEW-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000002439 beta secretase inhibitor Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- AKDNKSQXHBEBAS-UHFFFAOYSA-N carbamothioylsulfanyl n-methylidenecarbamodithioate Chemical compound NC(=S)SSC(=S)N=C AKDNKSQXHBEBAS-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000000114 cell free in vitro assay Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000037410 cognitive enhancement Effects 0.000 description 1
- 239000002475 cognitive enhancer Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 208000030251 communication disease Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 150000004908 diazepines Chemical class 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000007323 disproportionation reaction Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229960003748 edrophonium Drugs 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 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
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960002200 flunitrazepam Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229930184727 ginkgolide Natural products 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000004884 grey matter Anatomy 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000036046 immunoreaction Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000012623 in vivo measurement Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- RPCVIAXDAUMJJP-PZBABLGHSA-N ispronicline Chemical compound CN[C@@H](C)C\C=C\C1=CN=CC(OC(C)C)=C1 RPCVIAXDAUMJJP-PZBABLGHSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 229950006327 napsilate Drugs 0.000 description 1
- 210000000478 neocortex Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- 230000003557 neuropsychological effect Effects 0.000 description 1
- 238000010855 neuropsychological testing Methods 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- MICLTPPSCUXHJT-UHFFFAOYSA-M potassium;4-[3-(6-oxo-3h-purin-9-yl)propanoylamino]benzoate Chemical compound [K+].C1=CC(C(=O)[O-])=CC=C1NC(=O)CCN1C(NC=NC2=O)=C2N=C1 MICLTPPSCUXHJT-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 238000000235 small-angle X-ray scattering Methods 0.000 description 1
- 238000001464 small-angle X-ray scattering data Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 239000008174 sterile solution 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
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 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
- 210000003478 temporal lobe Anatomy 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 1
- 229960002447 thiram Drugs 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960003570 tramiprosate Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011820 transgenic animal model Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- XIEGSJAEZIGKSA-LUNMCBQDSA-N tropisetron hydrochloride Chemical compound Cl.C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 XIEGSJAEZIGKSA-LUNMCBQDSA-N 0.000 description 1
- 230000006453 vascular barrier function Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本出願は、全ての目的のためにここに参照により完全に本明細書に組み込まれる、2010年8月19日に出願の米国特許仮出願第61/401,907号への優先権および権益を主張する。
たは複数の構成成分のレベルの、CSFにおける低減、ならびに/またはAβ42/Aβ40比、Aβ42/Aβ38比、sAPPα、sAPPα/sAPPβ比、sAPPα/Aβ40比およびsAPPα/Aβ42比からなる群から選択される1つまたは複数の構成成分のレベルの、CSFにおける増加を含み、ならびに/または前記軽減は、哺乳動物の脳におけるプラーク負荷の低減を含み、ならびに/または前記軽減は、哺乳動物の脳におけるプラーク形成速度の低減を含み、ならびに/または前記軽減は、哺乳動物の認知能力の向上を含み、ならびに/または前記軽減は、哺乳動物の臨床認知症評価(CDR)の低下速度の向上、および/または安定化、および/または低減を含み、ならびに/または哺乳動物はヒトであり、前記軽減はヒトによって認知される生活の質の向上を含む。様々な実施形態では、化合物は、化合物を脳に到達させる(例えば、脳血液関門を通過または迂回させる)任意の様式で投与されてよい。特定の実施形態では、化合物は経口投与される。一部の実施形態では、投与は少なくとも3週間、例えば適宜少なくとも4、5、6、7、8、9、10、11、12週間、またはそれ以上にわたる。一部の実施形態では、投与は適宜少なくとも1、2、3、4、5、6、7、8、9、11、12カ月間、またはそれ以上にわたる。一部の実施形態では、投与は、対象の生涯の残りの期間である。特定の実施形態では、投与は、処置期間にわたって1日に1回、2回、3回または4回投与することを含む。特定の実施形態では、化合物またはそのアナログは、イソフォレティック(isophoretic)送達、経皮送達、エアゾール投与、吸入による投与、経口投与、静脈内投与および直腸投与からなる群から選択される経路による投与のために調剤される。特定の実施形態では、化合物またはそのアナログは、イソフォレティック(isophoretic)送達、経皮送達(例えば経皮パッチによる)、エアゾール投与、吸入による投与、経口投与、静脈内投与および直腸投与からなる群から選択される経路によって投与される。特定の実施形態では、化合物アセチルコリンエステラーゼ阻害剤(例えば、タクリン、イピダクリン、ガランタミン、ドネペジル、イコペジル、ザナペジル、リバスチグミン、フペルジンA、フェンセリン、フィゾスチグミン、ネオスチグミン、ピリドス
チグミン、アンベノニウム、デマルカリウム、エドロフォニウム、ラドスチギル、ウンゲレミンなど)は、前記化合物と併用投与されない。特定の実施形態では、トロピセトロン、ジスルフィラム、ホオノキオールおよびニメタゼパム、もしくはその薬学的に許容される塩(または他の薬学的に許容される形)、またはそのアナログもしくはその薬学的に許容される塩(または他の薬学的に許容される形)が、神経生理学的影響を有する対象に投与される唯一の剤である。特定の実施形態では、これらの化合物は、MCIの症状の軽減のために、またはMCIのADへの進行を阻害するか停止させるために対象に処方される唯一の活性剤である。
与される。一部の実施形態では、投与は少なくとも3週間、例えば適宜少なくとも4、5、6、7、8、9、10、11、12週間、またはそれ以上にわたる。一部の実施形態では、投与は適宜少なくとも1、2、3、4、5、6、7、8、9、11、12カ月間、またはそれ以上にわたる。一部の実施形態では、投与は、対象の生涯の残りの期間である。特定の実施形態では、投与は、処置期間にわたって1日に1回、2回、3回または4回投与することを含む。特定の実施形態では、化合物またはそのアナログは、イソフォレティック(isophoretic)送達、経皮送達、エアゾール投与、吸入による投与、経口投与、静脈内投与および直腸投与からなる群から選択される経路による投与のために調剤される。特定の実施形態では、化合物またはそのアナログは、イソフォレティック(isophoretic)送達、経皮送達(例えば経皮パッチによる)、エアゾール投与、吸入による投与、経口投与、静脈内投与および直腸投与からなる群から選択される経路によって投与される。特定の実施形態では、アセチルコリンエステラーゼ阻害剤(例えば、タクリン、イピダクリン、ガランタミン、ドネペジル、イコペジル、ザナペジル、リバスチグミン、フペルジンA、フェンセリン、フィゾスチグミン、ネオスチグミン、ピリドスチグミン、アンベノニウム、デマルカリウム、エドロフォニウム、ラドスチギル、ウンゲレミンなど)は、前記化合物と併用投与されない。特定の実施形態では、トロピセトロン、ジスルフィラム、ホオノキオールおよびニメタゼパム、またはその薬学的に許容される塩(または他の薬学的に許容される形)、またはそのアナログもしくはその薬学的に許容される塩(または他の薬学的に許容される形)が、神経生理学的影響を有する対象に投与される唯一の剤である。特定の実施形態では、これらの化合物は、アミロイド形成性病理(例えば、AD)の治療または予防のために対象に処方される唯一の活性剤である。
本明細書で用いるように、「投与すること」は、局所および全身の投与を指し、例えば、腸内、非経口、肺および局所/経皮投与を含む。本明細書に記載される方法で使用することができる化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオールおよび/またはニメタゼパム)の投与経路には、例えば、経口(経口(P.O.))投与、経鼻もしくは吸入投与、坐薬としての投与、局所接触、経皮送達(例えば、経皮パッチによる)、髄腔内(IT)投与、静脈内(「iv」)投与、腹腔内(「ip」)投与、筋肉内(「im」)投与、病巣内投与、または皮下(「sc」)投与、または対象への緩効性装置、例えばミニ浸透ポンプ、デポ製剤などの移植が含まれる。投与は、非経口および経粘膜(例えば、経口、経鼻、経膣、直腸、経皮)を含む任意の経路によることができる。非経口投与には、例えば、静脈内、筋肉内、動脈内、皮内、皮下、腹腔内、心室内、イオン泳動および脳内が含まれる。送達の他の様式には、リポソーム製剤、静脈内注入、経皮パッチなどの使用が含まれるが、これらに限定されない。
本明細書に記載される方法は、特定の化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオールおよびニメタゼパム、およびその様々な薬剤形態)が、非アミロイド形成性(「抗AD」)経路によってアミロイドベータ(A4)前駆体タンパク質(「APP」)のプロセシングを促進し、アミロイド形成性(「AD促進」)経路によってAPPのプロセシングを低減または阻害するという予想外の発見に一部基づく。これは、脳のアミロイドプラークに堆積することができるAβ、および神経毒性をもたらすことが知られている他のアミロイド形成促進断片の生成の低減をもたらすと考えられている。
本明細書に記載される方法は主に軽度の認知障害(MCI)およびアルツハイマー病(AD)との関連で詳述されるが、アミロイド症を特徴とする他の病理にそれらを等しく適用することができると考えられている。アミロイドプラーク形成を特徴とする健康状態の例示的であるが、非限定的な一覧をTable 1(表1)に示す。
軽度認知障害(MCI、別名初期の認知症または独立した記憶障害)は、彼らの年齢および教育から予想されるものを越えるが、彼らの日常活動を一般的にあまり妨害しない認知障害を有する個体に与えられる診断である(例えばPetersenら(1999) Arch. Neurol. 56(3): 303〜308頁を参照)。多くの例では、それは正常な加齢と認知症の間の境界または移行の段階であるとみなされる。MCIは様々な症状を提示することができるが、記憶喪失が主症状であるときには、それは「健忘性MCI」と呼ばれ、アルツハイマー病の危険因子としてしばしば見られる(例えば、Grundmanら(2004) Arch. Neurol. 61(1): 59〜66頁;およびインターネット上のen.wikipedia.org/wiki/Mild_cognitive_impairment-cite_note-Grundman-1を参照)。個体が記憶以外のドメインでの障害を有するときには、それは非健忘性の単一ドメインまたは複数ドメインのMCIとしばしば分類され、これらの個体は他の認知症(例えばレーヴィ小体を伴う認知症)に転換する可能性がより高いと考えられている。健忘性MCI患者はアルツハイマー病の神経病理的基準を満たすことができないが、患者は発達中のアルツハイマー病の移行段階にいる可能性があることを示唆する証拠がある。この仮定の移行段階にある患者は、新皮質での散在性のアミロイド、および内側側頭葉での頻繁な神経原線維濃縮体を実証した(Petersenら(2006) Arch. Neurol. 63(5): 665〜72頁)。
特定の実施形態では、本明細書に記載される方法は、アルツハイマー病(AD)の開始を予防するか減速すること、臨床AD診断へ対象が移行したときにADの重症度を低減すること、および/またはアルツハイマー病の1つまたは複数の症状を軽減することにおいて有益である。
本明細書に記載される方法は、1つまたは複数の化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオール、および/もしくはニメタゼパムまたはそれらの薬学的に許容される形)、および/またはそのアナログ、および/もしくはその薬学的に許容される形の投与が、脳におけるアミロイド沈着を特徴とする疾患、例えばアルツハイマー病の処置および予防で用いることができるという発見に一部基づく。
ホオノキオールの例示的な有用なアナログは、例えば、Kuribaraら、Pharmacol Biochem Behav. (2000) 67(3):597〜601頁; Luoら、Bioorganic & Medicinal Chemistry Letters、(2009) 19(16):4702〜4705頁;Esumiら、Bioorganic & Medicinal Chemistry Letters (2004) 14(10): 2621〜2625頁;Ahnら、Mol Cancer Res (2006) 4:621頁;Friedら、Antioxid Redox Signal.(2009) 11(5): 1139〜1148頁;および国際公開第2008/137420号に記載されている。
予防目的のためには、対象は無症状であってもよいが、本明細書に記載される1つまたは複数の環境、ライフスタイルまたは遺伝的危険因子を有することができ、および/または既定の閾値年齢であってもよい。対象は、無症状であってもよいが、遺伝子検査(例えば、ApoE4または他のAD関連突然変異)、画像化検査(例えば、ピッツバーグ化合物Bスキャン(PIBスキャン)または他の検査)、または当技術分野で公知である他の予測的検査に基づいてADの危険性が高いと判断されてもよい。あるいは、対象は、疾患の初期症状、例えば軽度の認知障害(MCI)の症状を示していてもよく、またはMCIを有すると診断されてもよい。そのような場合、化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオールおよび/またはニメタゼパム)、および/またはそのアナログの投与は、疾患の開始または疾患の後期段階へのMCIの進行、例えばアルツハイマー病への進行を予防することもしくは遅らせることができ、および/または発症したならば疾患の重症度を低減することができる。
様々な処置方法において、対象は既に疾患の症状を示すか、疾患を有すると診断されていてもよい。例えば、対象はMCIの症状を示すか、MCIを有すると診断されていてもよい。一部の実施形態では、対象はアルツハイマー病の症状を示すか、アルツハイマー病を有すると診断されていてもよい。そのような場合、化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオール、および/またはニメタゼパム)、および/またはそのアナログの投与は、疾患の症状の進行を反転させるか遅らせることができ、および/またはその重症度を低減することができる。
a.製剤
化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオール、および/またはニメタゼパム)および/またはそのアナログは、経口的、非経口的、(静脈内(IV)、筋肉内(IM)、デポIM、皮下(SQ)、およびデポSQ)、舌下、鼻腔内(吸入)、クモ膜下、経皮的(例えば、経皮パッチによって)、局所的、イオン泳動的または直腸に投与することができる。一般的に、剤形は、脳への送達(例えば、血液脳関門の通過)を促進するように選択される。これに関連して、本明細書に記載される化合物は脳へ容易に運ばれることが記されている。当業者に公知である剤形は、化合物の送達のために適する。
様々な実施形態では、化合物および/またはそのアナログは、経口的、非経口的(IV、IM、デポIM、SQ、およびデポSQ)、舌下、鼻腔内(吸入)、クモ膜下、経皮的(例えば、経皮パッチによって)、局所的または直腸に投与することができる。当業者に公知である剤形は、化合物および/またはそのアナログの送達のために適する。
特定の実施形態では、化合物および/またはそのアナログ(例えば、トロピセトロン、ジスルフィラム、ホオノキオールおよび/もしくはニメタゼパム、またはそのアナログ)は、MCIおよび/またはADを含む、脳におけるアミロイド沈着を特徴とする疾患を処置または予防するために用いられる他の治療薬または方法と一緒に用いることができる。そのような剤または方法には、以下のものが含まれる:アセチルコリンエステラーゼ阻害剤(非限定的に、例えば、(-)-フェンセリン鏡像異性体、タクリン、イピダクリン、ガランタミン、ドネペジル、イコペジル、ザナペジル、リバスチグミン、フペルジンA、フェンセリン、フィゾスチグミン、ネオスチグミン、ピリドスチグミン、アンベノニウム、デマルカリウム、エドロフォニウム、ラドスチギルおよびウンゲレミンを含む);NMDA受容体アンタゴニスト(非限定的に、例えば、メマンチンを含む);ムスカリン受容体アゴニスト(非限定的に、例えば、タルサクリジン、AF-102B、AF-267B (NGX-267)を含む);ニコチン受容体アゴニスト(非限定的に、例えば、イスプロニクリン(AZD-3480)を含む);ベータセクレターゼ阻害剤(非限定的に、例えば、ロジグリタゾンおよびピオグリタゾンを含むチアゾリジンジオンを含む);ガンマセクレターゼ阻害剤(非限定的に、例えば、MK-0752、E-2012、BMS-708163、PF-3084014、ベガセスタット(GSI-953)およびNIC5-15を含む);Aβ凝集阻害剤(非限定的に、例えば、クリオキノール(PBT1)、PBT2、トラミプロセート(ホモタウリン)、Scyllo-イノシトール(a.k.a.、scyllo-シクロヘキサンヘキサオール、AZD-103およびELND-005)、Aβ断片(非限定的に、例えば、バピノイゼマブを含む)による受動免疫療法、およびエピガロカテキン-3-没食子酸塩(EGCg)を含む);シクロオキシゲナーゼII阻害剤などの抗炎症剤;ビタミンEおよびギンコリドなどの抗酸化剤;免疫学的方法、例えばAβペプチドによる免疫化または抗Aβペプチド抗体の投与;スタチン;ならびに直接的または間接的な神経栄養剤、例えばCerebrolysin (商標)、AIT-082(Emilieu、2000、Arch. Neurol. 57:454頁)、ネトリン(Luorenco、2009、Cell Death Differ 16、655〜663頁)、Netrin模倣体、NGF、NGF模倣体、BDNFおよび将来の他の神経栄養剤、神経形成を促進する剤、例えば幹細胞療法および/または遺伝子療法。MCIおよび/またはADを含む、脳におけるアミロイド沈着を特徴とする疾患を処置または予防するために、トロピセトロン、ジスルフィラム、ホオノキオールおよび/またはニメタゼパムと併用することが有益であるさらなる薬理学的剤が、例えばMangialascheら、Lancet Neurol (2010) 9:702〜16頁に記載されている。
特定の理論に束縛されることなく、化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオールおよび/またはニメタゼパム)および/またはそのアナログは、非アミロイド形成経路によってAPPのプロセシングを促進し、および/またはアミロイド形成経路によってAPPのプロセシングを低減もしくは阻害すると考えられている。非アミロイド形成経路では、APPはAβ配列の中でα-セクレターゼによって先ず切断されて、APPsα外部ドメイン(「sAPPα」)を放出する。対照的に、β-セクレターゼがAβのアミノ末端でAPPを切断し、それによってAPPsβ外部ドメイン(「sAPPβ」)を放出するときに、アミロイド形成経路が開始される。非アミロイド形成およびアミロイド形成経路によるAPPプロセシングは当技術分野で公知であり、例えば、Xu, J Alzheimers Dis (2009) 16(2):211〜224頁およびDe Strooperら、Nat Rev Neurol (2010) 6(2):99〜107頁にレビューされている。
化合物および/またはそのアナログの阻害活性を実証するために用いることができる例示的なアッセイは、例えば、国際公開第00/17369号、国際公開第00/03819号および米国特許第5,942,400号および第5,744,346号に記載されている。そのようなアッセイは、無細胞インキュベーションで、または、α-セクレターゼおよび/もしくはβ-セクレターゼを発現する細胞とα-セクレターゼおよびβ-セクレターゼの切断部位を有するAPP基質を用いる細胞性インキュベーションで実施することができる。
相対的なα-セクレターゼ活性とβ-セクレターゼの活性、および/またはアミロイド形成性対非アミロイド形成性のAβオリゴマーを放出するAPPのプロセシングに対する対象の化合物の活性を評価するために、多くの細胞ベースのアッセイを用いることができる。化合物および/またはそのアナログの存在下または非存在下でのAPP基質とα-セクレターゼおよび/またはβ-セクレターゼ酵素との細胞内での接触は、化合物またはそのアナログのα-セクレターゼ促進活性および/またはβ-セクレターゼ阻害活性を実証するために用いることができる。好ましくは、化合物またはそのアナログの存在下でのアッセイは、阻害されない対照と比較して、β-セクレターゼ酵素活性の少なくとも約30%、最も好ましくは少なくとも約50%の阻害を提供する。他の実施形態では、化合物またはそのアナログの存在下でのアッセイは、化合物の存在しない対照アッセイと比較して、α-セクレターゼ酵素活性の少なくとも約30%、最も好ましくは少なくとも約50%の増加を提供する。
α-セクレターゼ活性および/またはβ-セクレターゼの相対的な活性、および/またはAβを放出するAPPのプロセシングに対する対象の化合物の活性を分析するために、様々な動物モデルを用いることができる。例えば、APP基質、α-セクレターゼおよび/またはβ-セクレターゼ酵素を発現するトランスジェニック動物は、化合物の阻害活性を実証するために用いることができる。特定のトランスジェニック動物モデルが、例えば、米国特許第5,877,399号;5,612,486号;5,387,742号;5,720,936号;5,850,003号;5,877,015号および5,811,633号、ならびにGanesら、1995、Nature 373:523頁に記載されている。ADの病態生理と関連する特徴を示す動物が好ましい。本明細書に記載されるトランスジェニックマウスへの化合物の投与は、化合物の阻害活性を実証するための代替方法を提供する。薬学的に有効な担体での、および適当な治療量で標的組織に到達する投与経路による化合物の投与も好ましい。
様々な実施形態では、処置の効果は、化合物(例えば、トロピセトロン、ジスルフィラム、ホオノキオール、および/またはニメタゼパム)および/またはそのアナログの投与が開始される前の疾患のパラメーターのベースライン測定を、化合物またはアナログが投与された後の1時点または複数時点における同じパラメーターと比較することによって判定することができる。測定することができる1つの例示的なパラメーターは、APPプロセシングのバイオマーカー(例えば、ペプチドオリゴマー)である。そのようなバイオマーカーには、それらに限定されないが、血液、血漿、血清、尿、粘液または脳脊髄液(CSF)の中の、sAPPα、p3(Aβ17〜42またはAβ17〜40)、sAPPβ、可溶性Aβ40、および/または可溶性Aβ42のレベルの増加である。sAPPαおよび/またはp3のレベルの増加ならびにsAPPβおよび/またはAPPneoのレベルの低下の検出は、処置が有効であることの指標である。逆に、sAPPαおよび/またはp3のレベルの低下、ならびに/あるいはsAPPβ、APPneo、タウまたはリン酸化タウ(pTau)のレベルの増加の検出は、処置が有効でないことの指標である。
以下の実施例は請求される発明を例示するために提供され、限定するためではない。
7W APPトランスフェクション細胞でのALPHALISA(登録商標)アッセイ
この実施例は、測定値sAPPα、Aβ42およびAPPneoのための実験的方法を提供する
J20 (PDAPPマウスモデル)初代培養神経細胞
この実施例は、初代培養神経細胞でのsAPPα、Aβ42およびAPPneoの測定のための実験的方法を提供する
マウス脳取り込みおよびバイオマーカー試験
この実施例は、PDAPPマウスモデルでの化合物の脳浸透ならびにsAPPα、Aβ40/42およびAPPneoに対する影響のin vivo測定のための実験的方法を提供する。
ALPHALISA分析:脳ホモジネートからのsAPPα(cat#: AL254C)、sAPPβ(cat#: AL232C)、Aβ40(cat#: AL275C)、Aβ42(cat#: AL276C)およびタウ(cat#: AL271C)を定量化するために、Perkin Elmer(PE)のALPHALISA (登録商標)キットを用いた。試料は、AlphaPlate-384(cat#: 6005350)に加えられる。受容体ビーズ抗体混合液の20マイクロリットル(μl)を、各5μlの脳脊髄液(CSF)試料に加え、室温で1時間インキュベートさせた。次に、25μlのドナービーズを加え、室温で30分間、暗所でインキュベートさせた。次にEnsPire 96ウェルプレートリーダー(Perkin-Elmer)で、蛍光を測定した。
トロピセトロン塩酸塩:マウスでの脳取り込み試験は、トロピセトロン塩酸塩が脳血管障壁をよく透過し、ピークの薬剤レベルで約3の脳/血漿比であることを実証した。5日間にわたる皮下(sc)経路による1キログラムにつき0.3ミリグラム(mpk)でのAPPトランスジェニック(Tg)マウスでの試験は、マウスの海馬(Hip)および嗅内皮質(ECx)でのsAPPαレベルの有意な増加、ならびにAβ40およびAβ42の両方のレベルの有意な低下をもたらす。トロピセトロンのこの用量は、正常な成人の1日5ミリグラムのヒト用量にほぼ同等である。結果を図4〜7に示す。
Claims (10)
- 哺乳動物におけるアミロイド形成過程を特徴とする軽度の認知障害(MCI)の症状の進行を遅らせるための医薬を製造するための、トロピセトロンもしくはその薬学的に許容される塩の使用方法であって、
前記の進行を遅らせることが、MCI(軽度の認知障害)のアルツハイマー病への進行を遅らせるか又は予防することからなり、
前記医薬が、可溶性Aβ40のレベルのCSF(脳脊髄液)における低減、および/もしくはsAPPαのレベルのCSF(脳脊髄液)における増加をもたらすものである、使用方法。 - 哺乳動物において非アミロイド形成経路によりアミロイド前駆体タンパク質(APP)のプロセシングを促進するための医薬を製造するための、トロピセトロンもしくはその薬学的に許容される塩の使用方法であって、
前記の非アミロイド形成経路によりアミロイド前駆体タンパク質(APP)のプロセシングを促進することが、可溶性Aβ40のレベルのCSF(脳脊髄液)における低減、および/もしくはsAPPαのレベルのCSF(脳脊髄液)における増加をもたらすことからなる、使用方法。 - トロピセトロンの薬学的に許容される塩を用いる、請求項1又は2に記載の使用方法。
- トロピセトロンもしくはその薬学的に許容される塩が経口投与のための医薬に製剤化される、請求項1又は2に記載の使用方法。
- 前記薬学的に許容される塩がHCl塩である、請求項1又は2に記載の使用方法。
- 前記哺乳動物がヒトである、請求項1又は2に記載の使用方法。
- 前記哺乳動物がアルツハイマー病を発症する危険がある、請求項1又は2に記載の使用方法。
- 前記哺乳動物がアルツハイマー病を有する家族性の危険を有する、請求項7に記載の使用方法。
- 前記哺乳動物が家族性アルツハイマー病(FAD)突然変異を有する、請求項7に記載の使用方法。
- 前記哺乳動物がAPOEε4対立遺伝子を有する、請求項7に記載の使用方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40190710P | 2010-08-19 | 2010-08-19 | |
US61/401,907 | 2010-08-19 | ||
PCT/US2011/048472 WO2012024616A1 (en) | 2010-08-19 | 2011-08-19 | Methods of treating miild cognitive impairment (mci) and related discorders |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016160482A Division JP2016193944A (ja) | 2010-08-19 | 2016-08-18 | 軽度の認知障害(mci)および関連障害の処置方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2013534256A JP2013534256A (ja) | 2013-09-02 |
JP2013534256A5 JP2013534256A5 (ja) | 2014-10-09 |
JP6250394B2 true JP6250394B2 (ja) | 2017-12-20 |
Family
ID=45605447
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013525003A Active JP6250394B2 (ja) | 2010-08-19 | 2011-08-19 | 軽度の認知障害(mci)および関連障害の処置方法 |
JP2016160482A Pending JP2016193944A (ja) | 2010-08-19 | 2016-08-18 | 軽度の認知障害(mci)および関連障害の処置方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016160482A Pending JP2016193944A (ja) | 2010-08-19 | 2016-08-18 | 軽度の認知障害(mci)および関連障害の処置方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US10449177B2 (ja) |
EP (1) | EP2605655B1 (ja) |
JP (2) | JP6250394B2 (ja) |
AU (1) | AU2011291506B2 (ja) |
BR (1) | BR112013003847A8 (ja) |
CA (1) | CA2808630A1 (ja) |
DK (1) | DK2605655T3 (ja) |
ES (1) | ES2705027T3 (ja) |
MX (1) | MX353096B (ja) |
WO (1) | WO2012024616A1 (ja) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012024616A1 (en) | 2010-08-19 | 2012-02-23 | Buck Institute For Age Research | Methods of treating miild cognitive impairment (mci) and related discorders |
CA2881189A1 (en) | 2012-08-07 | 2014-02-13 | Buck Institute For Research On Aging | Multi-component formulation for improving neurological function |
US20140371283A1 (en) | 2013-02-12 | 2014-12-18 | Buck Institute For Research On Aging | Hydantoins that modulate bace-mediated app processing |
US10369108B2 (en) | 2013-03-15 | 2019-08-06 | Mylan Laboratories, Inc. | Hot melt granulation formulations of poorly water-soluble active agents |
AU2015211021B2 (en) | 2014-01-28 | 2020-07-02 | Buck Institute For Research On Aging | Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders |
US20170216286A1 (en) | 2014-01-28 | 2017-08-03 | Mayo Foundation For Medical Education And Research | Killing senescent cells and treating senescence-associated conditions using a src inhibitor and a flavonoid |
WO2015143447A2 (en) | 2014-03-21 | 2015-09-24 | Alzheon, Inc. | Methods for treating neurological disorders |
EP3259274B1 (en) | 2015-02-18 | 2023-06-28 | Buck Institute for Research on Aging | Triazolopyridines and triazolopyrimidines that lower stress-induced p-tau |
CN107847504A (zh) * | 2015-05-18 | 2018-03-27 | 斯奈普泰克发展有限责任公司 | 淀粉状蛋白β的加兰他敏清除 |
KR102547164B1 (ko) * | 2015-09-10 | 2023-06-22 | 알제온, 인크. | 특정 환자 집단에서 신경퇴행성 장애를 치료하는 방법 |
WO2017100623A1 (en) | 2015-12-09 | 2017-06-15 | Brandeis University | Dbh inhibitors for treating or preventing memory loss |
US20180250249A1 (en) * | 2016-02-02 | 2018-09-06 | Alzheon, Inc. | Methods of treating neurodegenerative disorders in a particular population |
EP3455223B1 (en) | 2016-05-12 | 2023-11-08 | Buck Institute for Research on Aging | Compounds to promote normal processing of app |
CA3048660A1 (en) | 2017-01-03 | 2018-07-12 | Bioatla, Llc | Protein therapeutics for treatment of senescent cells |
JP7444797B2 (ja) | 2018-07-11 | 2024-03-06 | ルベド ライフ サイエンシズ, インク. | 老化細胞除去組成物及びその使用 |
CN110232679A (zh) * | 2019-05-24 | 2019-09-13 | 潘丹 | 一种阿尔茨海默症遗传生物标志物确定方法及系统 |
US20220313647A1 (en) | 2019-07-25 | 2022-10-06 | Tokyo University Of Science Foundation | Agent for treating, preventing or improving psychiatric and nervous system disorders or symptoms |
Family Cites Families (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
JPS5936675A (ja) | 1982-07-13 | 1984-02-28 | サンド・アクチエンゲゼルシヤフト | 二環性複素環式カルボン酸アザビシクロアルキルエステルまたはアミド |
CA2085127C (en) | 1990-06-15 | 2002-12-10 | Barbara Cordell | Transgenic non-human mammal displaying the amyloid-forming pathology of alzheimer's disease |
WO1992013069A1 (en) | 1991-01-21 | 1992-08-06 | Imperial College Of Science, Technology & Medicine | Test and model for alzheimer's disease |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5206264A (en) * | 1991-11-04 | 1993-04-27 | Cypros Pharmaceutical Corporation | Use of disulfiram to prevent cardiovascular damage |
EP0620849B1 (en) | 1992-01-07 | 2003-06-25 | Elan Pharmaceuticals, Inc. | Transgenic animal models for alzheimer's disease |
US5604102A (en) | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
DE69426571T2 (de) | 1993-10-27 | 2001-08-09 | Elan Pharm Inc | TRANSGENE TIERE, DIE APP Allele mit der schwedischen Mutation beherbergen |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
US5744346A (en) | 1995-06-07 | 1998-04-28 | Athena Neurosciences, Inc. | β-secretase |
US5942400A (en) | 1995-06-07 | 1999-08-24 | Elan Pharmaceuticals, Inc. | Assays for detecting β-secretase |
SE9600683D0 (sv) | 1996-02-23 | 1996-02-23 | Astra Ab | Azabicyclic esters of carbamic acids useful in therapy |
US6045829A (en) | 1997-02-13 | 2000-04-04 | Elan Pharma International Limited | Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers |
WO2000003819A1 (en) | 1998-07-17 | 2000-01-27 | The Penn State Research Foundation | Full form roll finishing technique |
US6331571B1 (en) | 1998-08-24 | 2001-12-18 | Sepracor, Inc. | Methods of treating and preventing attention deficit disorders |
KR20070013361A (ko) | 1998-09-24 | 2007-01-30 | 파마시아 앤드 업존 캄파니 엘엘씨 | 알츠하이머병 세크레타제 |
US6342496B1 (en) | 1999-03-01 | 2002-01-29 | Sepracor Inc. | Bupropion metabolites and methods of use |
US6337328B1 (en) | 1999-03-01 | 2002-01-08 | Sepracor, Inc. | Bupropion metabolites and methods of use |
ATE288415T1 (de) | 1999-04-05 | 2005-02-15 | Emisphere Tech Inc | Dinatrium-salze, monohydrate und ethanol-solvate |
US20040092511A1 (en) | 1999-12-10 | 2004-05-13 | Billstein Stephan Anthony | Pharmaceutical combinations and their use in treating gastrointestinal and abdominal viscera disorders |
US20070059367A1 (en) | 2000-06-06 | 2007-03-15 | Cherukuri S R | Drug Delivery System and Associated Methods |
US20020115727A1 (en) | 2000-12-04 | 2002-08-22 | Senanayake Chris H. | Synthesis, methods of using, and compositions of hydroxylated cyclobutylalkylamines |
US20020107244A1 (en) | 2001-02-02 | 2002-08-08 | Howard Harry R. | Combination treatment for depression |
EP1578719A4 (en) | 2002-10-25 | 2006-07-05 | Collegium Pharmaceutical Inc | P-HYDROXY-MILNACIPRAN STEREOISOMERS AND METHODS OF USING THE SAME |
US20040121010A1 (en) | 2002-10-25 | 2004-06-24 | Collegium Pharmaceutical, Inc. | Pulsatile release compositions of milnacipran |
FR2846559B1 (fr) | 2002-10-31 | 2007-06-15 | Centre Nat Rech Scient | Composition pharmaceutique pour la preparation d'un medicament destine a traiter et/ou a prevenir une pathologie liee a une conduite obsessionnelle |
US7148226B2 (en) | 2003-02-21 | 2006-12-12 | Agouron Pharmaceuticals, Inc. | Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same |
CN1922171B (zh) | 2004-02-26 | 2012-10-17 | Aska制药株式会社 | 嘧啶衍生物 |
CA2564059C (en) | 2004-04-21 | 2016-06-14 | Mear Holding B.V. | System for measuring pulsatile vascular resistance |
US8470846B2 (en) * | 2004-04-30 | 2013-06-25 | National University Corporation Chiba University | Remedy for psychoneurotic diseases |
US8193250B2 (en) * | 2004-10-22 | 2012-06-05 | Mount Sinai School Of Medicine | Compositions and methods for treating alzheimer's disease and related disorders and promoting a healthy nervous system |
WO2006069030A1 (en) | 2004-12-20 | 2006-06-29 | Collegium Pharmaceutical, Inc. | Pharmaceutical compositions for sleep disorders |
WO2006071995A1 (en) | 2004-12-23 | 2006-07-06 | Xenoport, Inc. | Serine amino acid derived prodrugs of propofol, compositions, uses and crystalline forms thereof |
EP1877093A2 (en) | 2005-04-15 | 2008-01-16 | Board of Trustees of Michigan State University | Ascorbate binding peptides |
GB0515090D0 (en) | 2005-07-22 | 2005-08-31 | Birmingham Res & Dev Ltd | Novel epilepsy treatment |
US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
EP1993542A1 (en) | 2006-03-01 | 2008-11-26 | Galderma Research & Development, S.N.C. | Method of treating inflammatory skin diseases using tropisetron, and pharmaceutical compositions thereof |
US20100183513A1 (en) * | 2006-11-24 | 2010-07-22 | Wolfgang Froestl | N-(methyl) -1h-pyrazol-3-amine, n-(methyl)-pyridin-2-amine and n-(methyl)-thiazol-2-amine derivatives for the treatment of diseases associated with amyloid or amyloid-like proteins, like e.g. alzheimer's |
WO2008074896A1 (en) | 2006-12-21 | 2008-06-26 | Prendergast Patrick T | Compositions and methods for treatment of chronic neurological disorders |
EP2933243B1 (en) | 2007-05-03 | 2017-11-01 | Jack L. Arbiser | Honokiol analogs and their use in treating cancers |
WO2009064505A1 (en) | 2007-11-16 | 2009-05-22 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Methods for treating visceral pain |
CL2007003877A1 (es) | 2007-12-28 | 2008-06-27 | Univ De Concepcion Lab Androma | Composicion farmaceutica que comprende un complejo de inclusion formado por disulfiram y una ciclodextrina; y su uso para el tratamiento de la dependencia de alcohol y cocaina. |
ES2527448T3 (es) | 2008-04-28 | 2015-01-23 | Zogenix, Inc. | Nuevas formulaciones para el tratamiento de la migraña |
KR101653707B1 (ko) | 2008-05-29 | 2016-09-02 | 알바니 몰레큘라 리써치, 인크. | 5-ht3 수용체 조절제, 이의 제조 방법, 및 그의 용도 |
JP5514827B2 (ja) * | 2008-09-25 | 2014-06-04 | バイオランド リミテッド | 4−o−メチルホノキオールを含有するアミロイド関連疾患の治療又は予防用組成物 |
US9622977B2 (en) | 2008-10-08 | 2017-04-18 | Bioplus Life Sciences Pvt, Ltd. | Sustained release drug delivery system |
US20100099701A1 (en) | 2008-10-20 | 2010-04-22 | Auspex Pharmaceuticals, Inc. | Isoquinolinone modulators of 5-ht3 receptors |
CN101444508B (zh) | 2008-12-29 | 2010-10-27 | 海南瑞基药物研究有限公司 | 一种注射用托烷司琼制剂及其制备方法 |
EP2432437A4 (en) | 2009-05-21 | 2012-12-19 | Bionex Pharmaceuticals Llc | TWO- AND ONE-LAYER DOSAGE FORMS |
US20110003005A1 (en) | 2009-07-06 | 2011-01-06 | Gopi Venkatesh | Methods of Treating PDNV and PONV with Extended Release Ondansetron Compositions |
US9790109B2 (en) * | 2010-04-30 | 2017-10-17 | General Electric Company | Method for sanitizing an electrodeionization device |
WO2012024616A1 (en) | 2010-08-19 | 2012-02-23 | Buck Institute For Age Research | Methods of treating miild cognitive impairment (mci) and related discorders |
KR101368587B1 (ko) | 2010-12-27 | 2014-03-05 | 주식회사 삼양바이오팜 | 오심 또는 구토 방지용 조성물 |
EP2508174A1 (en) | 2011-04-06 | 2012-10-10 | Ljiljana Sovic Brkicic | Pharmaceutical composition |
US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
EP2814491A4 (en) | 2012-02-18 | 2015-08-26 | Buck Inst For Res On Aging | FORMULATIONS AND METHODS FOR TREATING OR PROPHYLAXIS OF PRE-MCI AND / OR PRE-ALZHEIMER ILLNESSES |
-
2011
- 2011-08-19 WO PCT/US2011/048472 patent/WO2012024616A1/en active Application Filing
- 2011-08-19 JP JP2013525003A patent/JP6250394B2/ja active Active
- 2011-08-19 AU AU2011291506A patent/AU2011291506B2/en not_active Ceased
- 2011-08-19 ES ES11818848T patent/ES2705027T3/es active Active
- 2011-08-19 US US13/213,960 patent/US10449177B2/en active Active
- 2011-08-19 EP EP11818848.1A patent/EP2605655B1/en active Active
- 2011-08-19 DK DK11818848.1T patent/DK2605655T3/en active
- 2011-08-19 MX MX2013001917A patent/MX353096B/es active IP Right Grant
- 2011-08-19 BR BR112013003847A patent/BR112013003847A8/pt not_active IP Right Cessation
- 2011-08-19 CA CA2808630A patent/CA2808630A1/en not_active Abandoned
-
2016
- 2016-08-18 JP JP2016160482A patent/JP2016193944A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2012024616A1 (en) | 2012-02-23 |
BR112013003847A8 (pt) | 2017-12-26 |
JP2013534256A (ja) | 2013-09-02 |
EP2605655B1 (en) | 2018-10-24 |
EP2605655A4 (en) | 2014-01-08 |
US10449177B2 (en) | 2019-10-22 |
BR112013003847A2 (pt) | 2016-05-31 |
EP2605655A1 (en) | 2013-06-26 |
AU2011291506B2 (en) | 2016-07-28 |
JP2016193944A (ja) | 2016-11-17 |
DK2605655T3 (en) | 2019-02-04 |
MX353096B (es) | 2017-12-19 |
AU2011291506A1 (en) | 2013-03-14 |
MX2013001917A (es) | 2013-10-25 |
CA2808630A1 (en) | 2012-02-23 |
US20120071468A1 (en) | 2012-03-22 |
ES2705027T3 (es) | 2019-03-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6250394B2 (ja) | 軽度の認知障害(mci)および関連障害の処置方法 | |
US10835546B2 (en) | App specific BACE inhibitors (ASBIs) and uses thereof | |
US10766867B2 (en) | Hydantoins that modulate BACE-mediated APP processing | |
CN109563089B (zh) | 促进app正常加工的化合物 | |
US20150030683A1 (en) | Formulations and methods for the treatment or prophylaxis of pre-mci and/or pre-alzheimer's conditions | |
JP6830895B2 (ja) | ストレス誘発性p−tauを低下させるトリアゾロピリジン及びトリアゾロピリミジン | |
US20220041553A1 (en) | Apoe4-targeted theraputics that increase sirt1 | |
US20220265605A1 (en) | Methods of inducing autophagy using coumarin derivatives and related compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140819 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140819 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150706 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151002 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160106 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20160106 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20160418 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160818 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20160906 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20161014 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170919 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171122 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6250394 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |