EA028422B1 - Производные 1-[1-(бензоил)пирролидин-2-карбонил]пирролидин-2-карбонитрила - Google Patents
Производные 1-[1-(бензоил)пирролидин-2-карбонил]пирролидин-2-карбонитрила Download PDFInfo
- Publication number
- EA028422B1 EA028422B1 EA201590942A EA201590942A EA028422B1 EA 028422 B1 EA028422 B1 EA 028422B1 EA 201590942 A EA201590942 A EA 201590942A EA 201590942 A EA201590942 A EA 201590942A EA 028422 B1 EA028422 B1 EA 028422B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pyrrolidine
- formula
- carbonyl
- benzyloxy
- carbonitrile
- Prior art date
Links
- OACPBABDSINWMY-UHFFFAOYSA-N 1-(1-benzoylpyrrolidine-2-carbonyl)pyrrolidine-2-carbonitrile Chemical class C1CCC(C#N)N1C(=O)C1CCCN1C(=O)C1=CC=CC=C1 OACPBABDSINWMY-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 238000000034 method Methods 0.000 claims abstract description 78
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 44
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 230000002265 prevention Effects 0.000 claims abstract description 8
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 37
- -1 benzyloxy, phenylcarbonyloxy Chemical group 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 19
- 208000024827 Alzheimer disease Diseases 0.000 claims description 17
- 208000018737 Parkinson disease Diseases 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 208000019022 Mood disease Diseases 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 208000017194 Affective disease Diseases 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 230000003405 preventing effect Effects 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 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 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 239000004793 Polystyrene Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229920002223 polystyrene Polymers 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 230000003993 interaction Effects 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- ATQVBSVAXDRWFW-HBMCJLEFSA-N [(1r)-2-(4-hydroxyphenyl)-1-[[(2s)-1-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]ethyl]phosphonic acid Chemical compound C([C@@H](C(=O)NC(=O)[C@H](C(C)C)NC)N[C@@H](CC=1C=CC(O)=CC=1)P(O)(O)=O)C1=CC=CC=C1 ATQVBSVAXDRWFW-HBMCJLEFSA-N 0.000 claims description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 73
- 101001095266 Homo sapiens Prolyl endopeptidase Proteins 0.000 description 72
- 239000000203 mixture Substances 0.000 description 66
- 239000000243 solution Substances 0.000 description 52
- 238000012360 testing method Methods 0.000 description 48
- 241001465754 Metazoa Species 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- 238000000746 purification Methods 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 37
- 230000000694 effects Effects 0.000 description 36
- 229960002429 proline Drugs 0.000 description 34
- 239000003112 inhibitor Substances 0.000 description 29
- 238000004007 reversed phase HPLC Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- RDRBIXSNGAYLPT-UHFFFAOYSA-N CC1=CC=C(COC2=CC3=C(C=C2)C(NC(=O)OCC2C4=C(C=CC=C4)C4=C2C=CC=C4)C2=C(O3)C=CC=C2)C=C1 Chemical compound CC1=CC=C(COC2=CC3=C(C=C2)C(NC(=O)OCC2C4=C(C=CC=C4)C4=C2C=CC=C4)C2=C(O3)C=CC=C2)C=C1 RDRBIXSNGAYLPT-UHFFFAOYSA-N 0.000 description 23
- 239000012467 final product Substances 0.000 description 21
- 229940002612 prodrug Drugs 0.000 description 21
- 239000000651 prodrug Substances 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- 239000012453 solvate Substances 0.000 description 19
- 238000005859 coupling reaction Methods 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 230000002401 inhibitory effect Effects 0.000 description 17
- 238000012549 training Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 108090000185 alpha-Synuclein Proteins 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000000872 buffer Substances 0.000 description 15
- 239000011347 resin Substances 0.000 description 15
- 229920005989 resin Polymers 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 241000283984 Rodentia Species 0.000 description 14
- 102000003802 alpha-Synuclein Human genes 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 13
- OVCCGNWMGBKDIZ-UHFFFAOYSA-N 3,5-dimethoxy-4-phenylmethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OCC1=CC=CC=C1 OVCCGNWMGBKDIZ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000945 filler Substances 0.000 description 11
- 230000015654 memory Effects 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 230000035699 permeability Effects 0.000 description 8
- 229930182821 L-proline Natural products 0.000 description 7
- 230000008499 blood brain barrier function Effects 0.000 description 7
- 210000001218 blood-brain barrier Anatomy 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000013016 learning Effects 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000001934 delay Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000035939 shock Effects 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- MWAGUKZCDDRDCS-UHFFFAOYSA-N 1-nitro-4-(4-nitrophenoxy)benzene Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C([N+]([O-])=O)C=C1 MWAGUKZCDDRDCS-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 239000004698 Polyethylene Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000004770 neurodegeneration Effects 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 201000007201 aphasia Diseases 0.000 description 4
- 239000000823 artificial membrane Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000003920 cognitive function Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000011302 passive avoidance test Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- JMSVCTWVEWCHDZ-UHFFFAOYSA-N syringic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1O JMSVCTWVEWCHDZ-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LMRXUVWBKMOZHM-UHFFFAOYSA-N 3,4-dibenzoyloxy-5-methoxybenzoic acid Chemical compound C=1C=CC=CC=1C(=O)OC=1C(OC)=CC(C(O)=O)=CC=1OC(=O)C1=CC=CC=C1 LMRXUVWBKMOZHM-UHFFFAOYSA-N 0.000 description 3
- MDKAXOLGQLHQIP-UHFFFAOYSA-N 3-acetyloxy-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC(C)=O)=C1OC MDKAXOLGQLHQIP-UHFFFAOYSA-N 0.000 description 3
- NAMUJFYSOGQDCY-UHFFFAOYSA-N 3-methoxy-4,5-bis(phenylmethoxy)benzoic acid Chemical compound C=1C=CC=CC=1COC=1C(OC)=CC(C(O)=O)=CC=1OCC1=CC=CC=C1 NAMUJFYSOGQDCY-UHFFFAOYSA-N 0.000 description 3
- QNEQDTLNDBGFSC-UHFFFAOYSA-N 4-benzoyloxy-3,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC(=O)C1=CC=CC=C1 QNEQDTLNDBGFSC-UHFFFAOYSA-N 0.000 description 3
- MDUDZLWMGWNCIQ-UHFFFAOYSA-N 4-phenylmethoxy-3-(trifluoromethyl)benzoic acid Chemical compound FC(F)(F)C1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 MDUDZLWMGWNCIQ-UHFFFAOYSA-N 0.000 description 3
- 208000000044 Amnesia Diseases 0.000 description 3
- 208000031091 Amnestic disease Diseases 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 208000020358 Learning disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108090000189 Neuropeptides Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 201000004810 Vascular dementia Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 230000006986 amnesia Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 3
- 229940073608 benzyl chloride Drugs 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 201000003723 learning disability Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000006386 memory function Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 239000003495 polar organic solvent Substances 0.000 description 3
- 230000008092 positive effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 101150106357 slc32a1 gene Proteins 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 2
- WFIBQVFJXGQICQ-UHFFFAOYSA-N 3,4-O-Dimethylgallic acid Chemical compound COC1=CC(C(O)=O)=CC(O)=C1OC WFIBQVFJXGQICQ-UHFFFAOYSA-N 0.000 description 2
- AYEWLIDLBSBMJM-UHFFFAOYSA-N 3-(2,2-dimethylpropanoyloxy)-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC(=O)C(C)(C)C)=C1OC AYEWLIDLBSBMJM-UHFFFAOYSA-N 0.000 description 2
- POKWULIMSISXLX-UHFFFAOYSA-N 3-fluoro-4-phenylmethoxybenzoic acid Chemical compound FC1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 POKWULIMSISXLX-UHFFFAOYSA-N 0.000 description 2
- 208000006888 Agnosia Diseases 0.000 description 2
- 241001047040 Agnosia Species 0.000 description 2
- 206010003062 Apraxia Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 206010012218 Delirium Diseases 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 206010052804 Drug tolerance Diseases 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 2
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 102400000096 Substance P Human genes 0.000 description 2
- 101800003906 Substance P Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000012223 aqueous fraction Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000026781 habituation Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001078 lithium Drugs 0.000 description 2
- 229910052744 lithium Inorganic materials 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
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 2
- LVVUKXKEXOTUPV-UHFFFAOYSA-N methyl 3,4-dihydroxy-5-methoxybenzoate Chemical compound COC(=O)C1=CC(O)=C(O)C(OC)=C1 LVVUKXKEXOTUPV-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- ZMXJAEGJWHJMGX-UHFFFAOYSA-N methyl syringate Chemical compound COC(=O)C1=CC(OC)=C(O)C(OC)=C1 ZMXJAEGJWHJMGX-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229940127237 mood stabilizer Drugs 0.000 description 2
- 239000004050 mood stabilizer Substances 0.000 description 2
- PVRJOEAYRBQPLF-UHFFFAOYSA-N n-(2-hydroxypropyl)-n-(2-oxopropyl)nitrous amide Chemical compound CC(O)CN(N=O)CC(C)=O PVRJOEAYRBQPLF-UHFFFAOYSA-N 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 230000002981 neuropathic effect Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 230000036963 noncompetitive effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 125000001151 peptidyl group Chemical group 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000003649 prolyl endopeptidase inhibitor Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 102200036620 rs104893878 Human genes 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 2
- 229960000604 valproic acid Drugs 0.000 description 2
- 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
- 125000000229 (C1-C4)alkoxy group Chemical group 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
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- GMOYUTKNPLBTMT-UHFFFAOYSA-N 2-phenylmethoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCC1=CC=CC=C1 GMOYUTKNPLBTMT-UHFFFAOYSA-N 0.000 description 1
- GDTSJMKGXGJFGQ-UHFFFAOYSA-N 3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound O1B([O-])OB2OB([O-])OB1O2 GDTSJMKGXGJFGQ-UHFFFAOYSA-N 0.000 description 1
- XAUQFMSGRWJKEM-UHFFFAOYSA-N 3-(fluoromethyl)-4-phenylmethoxybenzoic acid Chemical compound FCC1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 XAUQFMSGRWJKEM-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IUSDEKNMCOUBEE-UHFFFAOYSA-N 3-fluoro-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(F)=C1 IUSDEKNMCOUBEE-UHFFFAOYSA-N 0.000 description 1
- CISXCTKEQYOZAM-UHFFFAOYSA-N 3-phenylmethoxybenzoic acid Chemical compound OC(=O)C1=CC=CC(OCC=2C=CC=CC=2)=C1 CISXCTKEQYOZAM-UHFFFAOYSA-N 0.000 description 1
- YAYTVCDEQBTDPJ-UHFFFAOYSA-N 4-(2,2-dimethylpropanoyloxy)-3,5-dimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC(=O)C(C)(C)C YAYTVCDEQBTDPJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DPVRVZQEDJVWLS-UHFFFAOYSA-N 4-hydroxy-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(O)C(C(F)(F)F)=C1 DPVRVZQEDJVWLS-UHFFFAOYSA-N 0.000 description 1
- AQSCHALQLXXKKC-UHFFFAOYSA-N 4-phenylmethoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 AQSCHALQLXXKKC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000036640 Asperger disease Diseases 0.000 description 1
- 201000006062 Asperger syndrome Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 241000283725 Bos Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FZBXWXKIYZAASU-UHFFFAOYSA-N ClCCl.N12CCCCCC2=NCCC1 Chemical compound ClCCl.N12CCCCCC2=NCCC1 FZBXWXKIYZAASU-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001035654 Homo sapiens 28 kDa heat- and acid-stable phosphoprotein Proteins 0.000 description 1
- 101000785915 Homo sapiens Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 Proteins 0.000 description 1
- 101000735427 Homo sapiens Poly(A) RNA polymerase, mitochondrial Proteins 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 201000006347 Intellectual Disability Diseases 0.000 description 1
- 101150092727 KLF10 gene Proteins 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 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
- 206010061285 Mental disorder due to a general medical condition Diseases 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 150000007945 N-acyl ureas Chemical class 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108700015930 Prolyl Oligopeptidases Proteins 0.000 description 1
- 101710178372 Prolyl endopeptidase Proteins 0.000 description 1
- 229940122210 Prolyl endopeptidase inhibitor Drugs 0.000 description 1
- 239000004365 Protease Substances 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
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 208000018642 Semantic dementia Diseases 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 229920002472 Starch Polymers 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
- 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
- 102100035000 Thymosin beta-4 Human genes 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010063661 Vascular encephalopathy Diseases 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000004523 agglutinating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- ORZXYSPOAVJYRU-UHFFFAOYSA-N benzyl 2-(2-formylpyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate Chemical compound O=CC1CCCN1C(=O)C1N(C(=O)OCC=2C=CC=CC=2)CCC1 ORZXYSPOAVJYRU-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 230000037411 cognitive enhancing Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 230000036992 cognitive tasks Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZYWSVSFFTZZPE-UHFFFAOYSA-M cyclopentyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C1CCCC1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WZYWSVSFFTZZPE-UHFFFAOYSA-M 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- OXZOLXJZTSUDOM-UHFFFAOYSA-N fluoro 2,2,2-trifluoroacetate Chemical compound FOC(=O)C(F)(F)F OXZOLXJZTSUDOM-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- KWCCUYSXAYTNKA-UHFFFAOYSA-N gallic acid-3-methyl ether Natural products COC1=CC(C(O)=O)=CC(O)=C1O KWCCUYSXAYTNKA-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 208000003906 hydrocephalus Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 230000028252 learning or memory Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001320 lysogenic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YFBSBLHMAWUCJB-UHFFFAOYSA-N methyl syringate Natural products COc1cc(cc(OC)c1O)C(=O)OO YFBSBLHMAWUCJB-UHFFFAOYSA-N 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
- 230000002025 microglial effect Effects 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000001343 mnemonic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KGDFDVHLEYUZLN-AWEZNQCLSA-N n-[(4-chlorophenyl)methyl]-4-[(2s)-2-formylpyrrolidin-1-yl]-4-oxobutanamide Chemical compound C1=CC(Cl)=CC=C1CNC(=O)CCC(=O)N1[C@H](C=O)CCC1 KGDFDVHLEYUZLN-AWEZNQCLSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001722 neurochemical effect Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000002957 persistent organic pollutant Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 description 1
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 description 1
- 102200036624 rs104893875 Human genes 0.000 description 1
- 102200036626 rs104893877 Human genes 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 108010079996 thymosin beta(4) Proteins 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000031836 visual learning Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Epidemiology (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12382446.8A EP2730571A1 (en) | 2012-11-12 | 2012-11-12 | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| PCT/EP2013/073460 WO2014072498A1 (en) | 2012-11-12 | 2013-11-11 | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201590942A1 EA201590942A1 (ru) | 2015-10-30 |
| EA028422B1 true EA028422B1 (ru) | 2017-11-30 |
Family
ID=47278735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201590942A EA028422B1 (ru) | 2012-11-12 | 2013-11-11 | Производные 1-[1-(бензоил)пирролидин-2-карбонил]пирролидин-2-карбонитрила |
Country Status (25)
| Country | Link |
|---|---|
| US (2) | US10125097B2 (enExample) |
| EP (2) | EP2730571A1 (enExample) |
| JP (1) | JP6203278B2 (enExample) |
| KR (1) | KR102151290B1 (enExample) |
| CN (1) | CN104903314B (enExample) |
| AU (1) | AU2013343430B2 (enExample) |
| BR (1) | BR112015010377A8 (enExample) |
| CA (1) | CA2890042C (enExample) |
| CY (1) | CY1118818T1 (enExample) |
| DK (1) | DK2917209T3 (enExample) |
| EA (1) | EA028422B1 (enExample) |
| ES (1) | ES2621672T3 (enExample) |
| HR (1) | HRP20170485T1 (enExample) |
| HU (1) | HUE032472T2 (enExample) |
| LT (1) | LT2917209T (enExample) |
| ME (1) | ME02706B (enExample) |
| MX (1) | MX367488B (enExample) |
| NZ (1) | NZ709096A (enExample) |
| PL (1) | PL2917209T3 (enExample) |
| PT (1) | PT2917209T (enExample) |
| RS (1) | RS55865B1 (enExample) |
| SI (1) | SI2917209T1 (enExample) |
| SM (1) | SMT201700202T1 (enExample) |
| WO (1) | WO2014072498A1 (enExample) |
| ZA (1) | ZA201504269B (enExample) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11504364B2 (en) | 2018-12-21 | 2022-11-22 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
| RU2803455C1 (ru) * | 2019-11-06 | 2023-09-13 | Юхань Корпорейшн | Пирролидиновые и пиперидиновые соединения |
| US11780821B2 (en) | 2017-12-15 | 2023-10-10 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2730571A1 (en) | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| EP3031458A1 (en) * | 2014-12-09 | 2016-06-15 | Iproteos S.L. | Use of 1-[(2-phenylcycloprop-1-yl)carbonyl]-2-[(1,3-thiazolidin-3-yl)carbonyl]perhydroindole in the treatment of schizophrenia-associated cognitive deficits |
| HUE068953T2 (hu) * | 2020-07-07 | 2025-02-28 | Accure Therapeutics S L | 1-[1-(4-benziloxi-3,5-difluor-benzoil)-4-fluor-pirrolidin-2-karbonil]-pirrolidin-2-karbonitril |
| MY208099A (en) * | 2020-12-28 | 2025-04-15 | Sarawak Biodiversity Council | Compound for treating neurodegenerative diseases and its isolation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003004468A1 (en) * | 2001-07-04 | 2003-01-16 | Orion Corporation | Compounds having prolyl oligopeptidase inhibitory activity, methods for their preparation and their use |
| WO2004060862A2 (en) * | 2003-01-03 | 2004-07-22 | Orion Corporation | Compounds having prolyl oligopeptidase inhibitory activity |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2084412C (en) * | 1990-06-04 | 2000-05-09 | W. Stephen Faraci | Pyrrolidine and thiazolidine amides |
| US6159938A (en) | 1994-11-21 | 2000-12-12 | Cortech, Inc. | Serine protease inhibitors comprising α-keto heterocycles |
| HUT76640A (en) * | 1995-08-17 | 1997-10-28 | Chinoin Gyogyszer Es Vegyeszet | Compounds of pharmaceutical activity cyclic amide derivatives, pharmaceutical compositions containing them, process for producing them and their use |
| DE19603510A1 (de) | 1996-02-01 | 1997-08-07 | Knoell Hans Forschung Ev | Die Verwendung von Terrecyclolsäure A und Terrecyclolsäure A-Derivate als neue Inhibitoren der humanen Prolyl-Oligopeptidase |
| BR0112580A (pt) * | 2000-07-19 | 2003-06-17 | Hoffmann La Roche | Compostos, composições farmacêuticas que contêm os mesmos, utilização desses compostos, processo para tratamento terapêutico e/ou profilático e processo para a preparação desses compostos |
| FI20031018A0 (fi) | 2003-07-04 | 2003-07-04 | Orion Corp | Parannus aivovammasta toipumiseen |
| WO2005027934A1 (ja) | 2003-09-24 | 2005-03-31 | Nippon Kayaku Kabushiki Kaisha | プロリルオリゴペプチダーゼ阻害剤 |
| US7667044B2 (en) | 2003-11-03 | 2010-02-23 | Probiodrug Ag | Compounds for the treatment of neurological disorders |
| EP1760076A1 (en) * | 2005-09-02 | 2007-03-07 | Ferring B.V. | FAP Inhibitors |
| ES2302473B1 (es) | 2006-12-22 | 2009-06-12 | Universidad De Barcelona | Agente terapeutico para el tratamiento del desorden afectivo bipolar en mamiferos. |
| EP2389176A4 (en) * | 2009-01-23 | 2012-08-01 | Univ Sydney | NEW THERAPY FOR METABOLISM DISEASE |
| EP2730571A1 (en) | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
-
2012
- 2012-11-12 EP EP12382446.8A patent/EP2730571A1/en not_active Withdrawn
-
2013
- 2013-11-11 HR HRP20170485TT patent/HRP20170485T1/hr unknown
- 2013-11-11 CN CN201380059126.XA patent/CN104903314B/zh active Active
- 2013-11-11 DK DK13794837.8T patent/DK2917209T3/en active
- 2013-11-11 HU HUE13794837A patent/HUE032472T2/en unknown
- 2013-11-11 ME MEP-2017-76A patent/ME02706B/me unknown
- 2013-11-11 BR BR112015010377A patent/BR112015010377A8/pt not_active Application Discontinuation
- 2013-11-11 PL PL13794837T patent/PL2917209T3/pl unknown
- 2013-11-11 LT LTEP13794837.8T patent/LT2917209T/lt unknown
- 2013-11-11 RS RS20170362A patent/RS55865B1/sr unknown
- 2013-11-11 SM SM20170202T patent/SMT201700202T1/it unknown
- 2013-11-11 SI SI201330601A patent/SI2917209T1/sl unknown
- 2013-11-11 EP EP13794837.8A patent/EP2917209B1/en active Active
- 2013-11-11 NZ NZ709096A patent/NZ709096A/en unknown
- 2013-11-11 JP JP2015541169A patent/JP6203278B2/ja active Active
- 2013-11-11 EA EA201590942A patent/EA028422B1/ru not_active IP Right Cessation
- 2013-11-11 US US14/436,715 patent/US10125097B2/en active Active
- 2013-11-11 AU AU2013343430A patent/AU2013343430B2/en active Active
- 2013-11-11 ES ES13794837.8T patent/ES2621672T3/es active Active
- 2013-11-11 WO PCT/EP2013/073460 patent/WO2014072498A1/en not_active Ceased
- 2013-11-11 MX MX2015005931A patent/MX367488B/es active IP Right Grant
- 2013-11-11 KR KR1020157015736A patent/KR102151290B1/ko active Active
- 2013-11-11 CA CA2890042A patent/CA2890042C/en active Active
- 2013-11-11 PT PT137948378T patent/PT2917209T/pt unknown
-
2015
- 2015-06-12 ZA ZA2015/04269A patent/ZA201504269B/en unknown
-
2017
- 2017-04-06 CY CY20171100410T patent/CY1118818T1/el unknown
-
2018
- 2018-09-26 US US16/142,907 patent/US10611727B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003004468A1 (en) * | 2001-07-04 | 2003-01-16 | Orion Corporation | Compounds having prolyl oligopeptidase inhibitory activity, methods for their preparation and their use |
| WO2004060862A2 (en) * | 2003-01-03 | 2004-07-22 | Orion Corporation | Compounds having prolyl oligopeptidase inhibitory activity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11780821B2 (en) | 2017-12-15 | 2023-10-10 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
| US11504364B2 (en) | 2018-12-21 | 2022-11-22 | Praxis Biotech LLC | Inhibitors of fibroblast activation protein |
| RU2803455C1 (ru) * | 2019-11-06 | 2023-09-13 | Юхань Корпорейшн | Пирролидиновые и пиперидиновые соединения |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10611727B2 (en) | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives | |
| US11566016B2 (en) | MAP kinase modulators and uses thereof | |
| KR20170008320A (ko) | 니코틴아미드 리보시드 유사체 및 그의 제약 조성물 및 용도 | |
| KR20180102052A (ko) | 조현병, 양극성 장애, 인지 손상 및 주요 우울 장애의 치료를 위한 비전형적 항정신병약과 nmda 조절제의 약제학적 병용 | |
| US20250282771A1 (en) | Tetrahydroisoquinoline heterobifunctional bcl-xl degraders | |
| EP3031458A1 (en) | Use of 1-[(2-phenylcycloprop-1-yl)carbonyl]-2-[(1,3-thiazolidin-3-yl)carbonyl]perhydroindole in the treatment of schizophrenia-associated cognitive deficits | |
| EP4178945B1 (en) | 1-[1-(4-benzyloxy-3,5-difluoro-benzoyl)-4-fluoro-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile | |
| HK1214597B (en) | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives | |
| RU2841064C1 (ru) | 1-[1-(4-бензилокси-3,5-дифтор-бензоил)-4-фтор-пирролидин-2-карбонил]-пирролидин-2-карбонитрил | |
| HK40084881A (en) | 1-[1-(4-benzyloxy-3,5-difluoro-benzoyl)-4-fluoro-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile | |
| HK40084881B (en) | 1-[1-(4-benzyloxy-3,5-difluoro-benzoyl)-4-fluoro-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile | |
| JP2026509274A (ja) | ソルチリン活性の修飾剤 | |
| CN119451944A (zh) | Prep结合配体 | |
| KR20250115893A (ko) | 섬유아세포 활성화 단백질에 의해 활성화되는 프로드러그 화합물 | |
| JP2026509826A (ja) | ソルチリン活性の修飾剤 | |
| WO2025227119A9 (en) | Myeloperoxidase fluorescence imaging | |
| JP2026509275A (ja) | ソルチリン修飾剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG TJ TM |