TW201902887A - 做為血漿激肽釋放酶抑制劑之雜芳基甲醯胺衍生物 - Google Patents
做為血漿激肽釋放酶抑制劑之雜芳基甲醯胺衍生物 Download PDFInfo
- Publication number
- TW201902887A TW201902887A TW107113453A TW107113453A TW201902887A TW 201902887 A TW201902887 A TW 201902887A TW 107113453 A TW107113453 A TW 107113453A TW 107113453 A TW107113453 A TW 107113453A TW 201902887 A TW201902887 A TW 201902887A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- methyl
- compound
- mixture
- minutes
- Prior art date
Links
- 102000003827 Plasma Kallikrein Human genes 0.000 title abstract description 34
- 108090000113 Plasma Kallikrein Proteins 0.000 title abstract description 34
- 229940127379 Kallikrein Inhibitors Drugs 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 238000011282 treatment Methods 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims description 239
- 239000000203 mixture Substances 0.000 claims description 167
- 239000003814 drug Substances 0.000 claims description 32
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 27
- 201000011190 diabetic macular edema Diseases 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229940124597 therapeutic agent Drugs 0.000 claims description 23
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 20
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000000969 carrier Substances 0.000 claims description 11
- 208000002249 Diabetes Complications Diseases 0.000 claims description 10
- 206010012655 Diabetic complications Diseases 0.000 claims description 10
- 230000002207 retinal effect Effects 0.000 claims description 10
- 230000008728 vascular permeability Effects 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 206010033307 Overweight Diseases 0.000 claims description 3
- 229940125708 antidiabetic agent Drugs 0.000 claims description 3
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- 208000030533 eye disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 46
- 201000010099 disease Diseases 0.000 abstract description 40
- 230000005764 inhibitory process Effects 0.000 abstract description 16
- 239000002585 base Substances 0.000 description 143
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 124
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 92
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 90
- -1 such tautomers Chemical class 0.000 description 71
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- 238000001819 mass spectrum Methods 0.000 description 63
- 239000002904 solvent Substances 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 37
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 37
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 34
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 238000003818 flash chromatography Methods 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 238000012360 testing method Methods 0.000 description 25
- 208000024891 symptom Diseases 0.000 description 24
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 150000001412 amines Chemical class 0.000 description 23
- BSKHPKMHTQYZBB-UHFFFAOYSA-N alpha-methylpyridine Natural products CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000000872 buffer Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 238000011156 evaluation Methods 0.000 description 18
- 208000001344 Macular Edema Diseases 0.000 description 17
- 229910004809 Na2 SO4 Inorganic materials 0.000 description 17
- 229910021529 ammonia Inorganic materials 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- 238000004007 reversed phase HPLC Methods 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
- 206010064930 age-related macular degeneration Diseases 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N gamma-methylpyridine Natural products CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 16
- 208000002780 macular degeneration Diseases 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 239000003112 inhibitor Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- 239000007821 HATU Substances 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 229910003002 lithium salt Inorganic materials 0.000 description 13
- 238000005259 measurement Methods 0.000 description 13
- GHBUVDSNXSMDMM-UHFFFAOYSA-N 6,6-difluoro-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(F)(F)C21 GHBUVDSNXSMDMM-UHFFFAOYSA-N 0.000 description 12
- 206010058202 Cystoid macular oedema Diseases 0.000 description 12
- 201000010206 cystoid macular edema Diseases 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 239000013067 intermediate product Substances 0.000 description 12
- 208000005189 Embolism Diseases 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 229940088598 enzyme Drugs 0.000 description 11
- 159000000002 lithium salts Chemical class 0.000 description 11
- 230000002062 proliferating effect Effects 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 108010054265 Factor VIIa Proteins 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 206010030113 Oedema Diseases 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- 229940012414 factor viia Drugs 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 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 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 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 description 9
- 206010038934 Retinopathy proliferative Diseases 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- 208000019553 vascular disease Diseases 0.000 description 7
- 208000017442 Retinal disease Diseases 0.000 description 6
- 206010038923 Retinopathy Diseases 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 6
- 230000005284 excitation Effects 0.000 description 6
- 150000004677 hydrates Chemical class 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 6
- 235000010378 sodium ascorbate Nutrition 0.000 description 6
- 229960005055 sodium ascorbate Drugs 0.000 description 6
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- WBRPPQHUNQRULX-XCUBXKJBSA-N (5R)-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCc2c1ccnc2N WBRPPQHUNQRULX-XCUBXKJBSA-N 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 206010025415 Macular oedema Diseases 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 5
- DXPIZCZNFUTPEI-UHFFFAOYSA-O diphenylphosphanium;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1[PH2+]C1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-O 0.000 description 5
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000007937 lozenge Substances 0.000 description 5
- 201000010230 macular retinal edema Diseases 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- ZSZJUTYMOQAERO-UHFFFAOYSA-N 2h-pyridine-1,5-diamine Chemical compound NN1CC=CC(N)=C1 ZSZJUTYMOQAERO-UHFFFAOYSA-N 0.000 description 4
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 4
- 239000005995 Aluminium silicate Substances 0.000 description 4
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 108010071241 Factor XIIa Proteins 0.000 description 4
- 108010080805 Factor XIa Proteins 0.000 description 4
- 108010074860 Factor Xa Proteins 0.000 description 4
- 101001091365 Homo sapiens Plasma kallikrein Proteins 0.000 description 4
- 102100038297 Kallikrein-1 Human genes 0.000 description 4
- 101710176219 Kallikrein-1 Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 102100034869 Plasma kallikrein Human genes 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 235000012211 aluminium silicate Nutrition 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 208000006752 brain edema Diseases 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 210000001957 retinal vein Anatomy 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 3
- URRCBZGTKZFEQQ-YCBDHFTFSA-N (5R)-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine dihydrochloride Chemical compound Cl.Cl.Cc1cc2[C@H](N)CCc2c(N)n1 URRCBZGTKZFEQQ-YCBDHFTFSA-N 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- BVCCCDHBLPVHFK-UHFFFAOYSA-N 6,6-difluoro-3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2C(F)(F)C21 BVCCCDHBLPVHFK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910018404 Al2 O3 Inorganic materials 0.000 description 3
- 206010048962 Brain oedema Diseases 0.000 description 3
- 125000006519 CCH3 Chemical group 0.000 description 3
- 108010079356 FIIa Proteins 0.000 description 3
- 206010019860 Hereditary angioedema Diseases 0.000 description 3
- 101100288141 Homo sapiens KLKB1 gene Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 208000022873 Ocular disease Diseases 0.000 description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003593 chromogenic compound Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 3
- 238000005192 partition Methods 0.000 description 3
- 239000012466 permeate Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- 229940012957 plasmin Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical compound OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- ZYIOWGKUAZOFQG-MRXNPFEDSA-N (5R)-1-N-[(2,4-dimethoxyphenyl)methyl]-3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine Chemical compound COC1=C(C=CC(=C1)OC)CNC1=NC(=CC2=C1CC[C@H]2N)C ZYIOWGKUAZOFQG-MRXNPFEDSA-N 0.000 description 2
- UEZYVFWKVAESRP-OAHLLOKOSA-N (5R)-1-N-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine Chemical compound COc1ccc(CNc2nccc3[C@H](N)CCc23)c(OC)c1 UEZYVFWKVAESRP-OAHLLOKOSA-N 0.000 description 2
- WQQDXDGGJBEHPA-SSDOTTSWSA-N (5R)-6,7-dihydro-5H-cyclopenta[c]pyridine-1,5-diamine Chemical compound N[C@@H]1CCc2c1ccnc2N WQQDXDGGJBEHPA-SSDOTTSWSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RLUJDZHBZDTSKK-UHFFFAOYSA-N 1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-methylpyridin-3-yl]methyl]triazole-4-carboxylic acid Chemical compound Cc1cc(ncc1Cn1cc(nn1)C(O)=O)N1CC2CC2C1 RLUJDZHBZDTSKK-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WJXYUEOVOQGJGV-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2CC21 WJXYUEOVOQGJGV-UHFFFAOYSA-N 0.000 description 2
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000028185 Angioedema Diseases 0.000 description 2
- 206010059245 Angiopathy Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 2
- NPTGVXJOQFLJER-JOCHJYFZSA-N COC1=C(C=CC(=C1)OC)CNC1=NC(=CC2=C1CC[C@H]2N1C(C2=CC=CC=C2C1=O)=O)C Chemical compound COC1=C(C=CC(=C1)OC)CNC1=NC(=CC2=C1CC[C@H]2N1C(C2=CC=CC=C2C1=O)=O)C NPTGVXJOQFLJER-JOCHJYFZSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NYNKCGWJPNZJMI-UHFFFAOYSA-N Clebopride malate Chemical compound [O-]C(=O)C(O)CC(O)=O.COC1=CC(N)=C(Cl)C=C1C(=O)NC1CC[NH+](CC=2C=CC=CC=2)CC1 NYNKCGWJPNZJMI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 108010000487 High-Molecular-Weight Kininogen Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102100035792 Kininogen-1 Human genes 0.000 description 2
- 108010093008 Kinins Proteins 0.000 description 2
- 102000002397 Kinins Human genes 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 201000010183 Papilledema Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 206010036346 Posterior capsule opacification Diseases 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 206010038886 Retinal oedema Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960000633 dextran sulfate Drugs 0.000 description 2
- 239000000385 dialysis solution Substances 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 208000011325 dry age related macular degeneration Diseases 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 206010014801 endophthalmitis Diseases 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000002390 heteroarenes Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 2
- 238000013021 overheating Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229940126155 plasma kallikrein inhibitor Drugs 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 201000011195 retinal edema Diseases 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- PJFSUJMJVYGASC-HKBOAZHASA-N (2r)-2-amino-n-[(2s)-1-[[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-3-phenylpropanamide Chemical compound C([C@@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)CCl)C1=CC=CC=C1 PJFSUJMJVYGASC-HKBOAZHASA-N 0.000 description 1
- YDMBNDUHUNWWRP-VJBWXMMDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]piperidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)C1=CC=CC=C1 YDMBNDUHUNWWRP-VJBWXMMDSA-N 0.000 description 1
- CAJXYXPLLJDEOB-SLFFLAALSA-N (2s)-6-amino-2-[[(2s)-2-[[(2r)-2-amino-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-n-(4-nitrophenyl)hexanamide Chemical compound CC(C)[C@@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 CAJXYXPLLJDEOB-SLFFLAALSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- KQJTXYQXRHCWKW-PJSBSAQXSA-N (4s)-4-[[(2s,3s)-2-benzamido-3-methylpentanoyl]amino]-5-[[2-[[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-5-oxopentanoic acid;hydrochloride Chemical compound Cl.N([C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)C(=O)C1=CC=CC=C1 KQJTXYQXRHCWKW-PJSBSAQXSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- AZGLGFYJRMZLHR-UHFFFAOYSA-N 1-[(6-fluoro-2-methylpyridin-3-yl)methyl]pyrazole-4-carboxylic acid Chemical compound FC1=CC=C(C(=N1)C)CN1N=CC(=C1)C(=O)O AZGLGFYJRMZLHR-UHFFFAOYSA-N 0.000 description 1
- JMEOCTCKQIROKH-UHFFFAOYSA-N 1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpyridin-3-yl]methyl]-3-(difluoromethyl)pyrazole-4-carboxylic acid Chemical compound C12CN(CC2C1)C1=CC=C(C(=N1)C)CN1N=C(C(=C1)C(=O)O)C(F)F JMEOCTCKQIROKH-UHFFFAOYSA-N 0.000 description 1
- XCIKKMPJRBPYSL-UHFFFAOYSA-N 1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpyridin-3-yl]methyl]-3-methoxypyrazole-4-carboxylic acid Chemical compound C12CN(CC2C1)C1=CC=C(C(=N1)C)CN1N=C(C(=C1)C(=O)O)OC XCIKKMPJRBPYSL-UHFFFAOYSA-N 0.000 description 1
- TWRSQCKWMHHGJV-UHFFFAOYSA-N 1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methylpyridin-3-yl]methyl]pyrazole-4-carboxylic acid Chemical compound C12CN(CC2C1)C1=CC=C(C(=N1)C)CN1N=CC(=C1)C(=O)O TWRSQCKWMHHGJV-UHFFFAOYSA-N 0.000 description 1
- OMPQTMWKJLUADZ-UHFFFAOYSA-N 1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-methylpyridin-3-yl]methyl]pyrazole-4-carboxylic acid Chemical compound Cc1cc(ncc1Cn1cc(cn1)C(O)=O)N1CC2CC2C1 OMPQTMWKJLUADZ-UHFFFAOYSA-N 0.000 description 1
- 229940124681 11 beta HSD inhibitor Drugs 0.000 description 1
- OGKSTJGMWPQRER-UHFFFAOYSA-N 2-(3-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindole-1,3-dione Chemical compound CC1=CC2=C(C=N1)CCC2N1C(C2=CC=CC=C2C1=O)=O OGKSTJGMWPQRER-UHFFFAOYSA-N 0.000 description 1
- XLIQGUVLNUVKQA-OAQYLSRUSA-N 2-[(5R)-1-[(2,4-dimethoxyphenyl)methylamino]-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]isoindole-1,3-dione Chemical compound COC1=C(CNC2=NC=CC=3[C@@H](CCC2=3)N2C(C3=CC=CC=C3C2=O)=O)C=CC(=C1)OC XLIQGUVLNUVKQA-OAQYLSRUSA-N 0.000 description 1
- WBSCMEPYFQFRLU-CQSZACIVSA-N 2-[(5R)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl]isoindole-1,3-dione Chemical compound C1=NC=CC=2[C@@H](CCC1=2)N1C(C2=CC=CC=C2C1=O)=O WBSCMEPYFQFRLU-CQSZACIVSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical compound C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 description 1
- SAQAERNKMHATDZ-UHFFFAOYSA-N 2-bromo-1h-pyrrole Chemical compound BrC1=CC=CN1 SAQAERNKMHATDZ-UHFFFAOYSA-N 0.000 description 1
- MANJIGKYCYWWBD-UHFFFAOYSA-N 2-chloro-2-oxoacetic acid Chemical compound OC(=O)C(Cl)=O MANJIGKYCYWWBD-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
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- NCTCZAISXOQDKD-UHFFFAOYSA-N 5-azaspiro[2.4]heptane;hydrochloride Chemical compound Cl.C1CC11CNCC1 NCTCZAISXOQDKD-UHFFFAOYSA-N 0.000 description 1
- LIHAMNSEAAPIRM-UHFFFAOYSA-N 5-trimethylsilylpent-4-yn-1-ol Chemical compound C[Si](C)(C)C#CCCCO LIHAMNSEAAPIRM-UHFFFAOYSA-N 0.000 description 1
- MLCUMJCCPMSERM-UHFFFAOYSA-N 5-trimethylsilylpent-4-ynal Chemical compound C[Si](C)(C)C#CCCC=O MLCUMJCCPMSERM-UHFFFAOYSA-N 0.000 description 1
- KHWHYHFZHBCYDB-UHFFFAOYSA-N 6,7-dihydrocyclopenta[c]pyridin-5-one Chemical compound N1=CC=C2C(=O)CCC2=C1 KHWHYHFZHBCYDB-UHFFFAOYSA-N 0.000 description 1
- ILGPMPQGXOQTTN-UHFFFAOYSA-N 7-trimethylsilylhepta-1,6-diyn-3-ol Chemical compound C[Si](C)(C)C#CCCC(O)C#C ILGPMPQGXOQTTN-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 206010060934 Allergic oedema Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 101100460776 Arabidopsis thaliana NPY2 gene Proteins 0.000 description 1
- 101100460788 Arabidopsis thaliana NPY5 gene Proteins 0.000 description 1
- 208000022211 Arteriovenous Malformations Diseases 0.000 description 1
- 102000017916 BDKRB1 Human genes 0.000 description 1
- 108060003359 BDKRB1 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102000010183 Bradykinin receptor Human genes 0.000 description 1
- 108050001736 Bradykinin receptor Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- NYLSANHUHCIJMZ-UHFFFAOYSA-N C12CN(CC2C1)C1=CC=C(C(=N1)C)CN1N=C(C(=C1)C(=O)O)C Chemical compound C12CN(CC2C1)C1=CC=C(C(=N1)C)CN1N=C(C(=C1)C(=O)O)C NYLSANHUHCIJMZ-UHFFFAOYSA-N 0.000 description 1
- SDEGKMYKNLXPAS-UHFFFAOYSA-N C12CN(CC2C1)C=1C=CN(C(N=1)C)CO Chemical compound C12CN(CC2C1)C=1C=CN(C(N=1)C)CO SDEGKMYKNLXPAS-UHFFFAOYSA-N 0.000 description 1
- HFSKUGLKSGRBPW-UHFFFAOYSA-N C1CC11CN(CC1)C1=CC=C(C(=N1)C)CN1N=CC(=C1)C(=O)O Chemical compound C1CC11CN(CC1)C1=CC=C(C(=N1)C)CN1N=CC(=C1)C(=O)O HFSKUGLKSGRBPW-UHFFFAOYSA-N 0.000 description 1
- LJYLJFRMLZVFDP-UHFFFAOYSA-N CC1=CC2=C(C(=N1)[Si](C)(C)C)CCC2O Chemical compound CC1=CC2=C(C(=N1)[Si](C)(C)C)CCC2O LJYLJFRMLZVFDP-UHFFFAOYSA-N 0.000 description 1
- SMDNEBMLZXELGQ-UHFFFAOYSA-N CC1=CC2=C(C=N1)CCC2O Chemical compound CC1=CC2=C(C=N1)CCC2O SMDNEBMLZXELGQ-UHFFFAOYSA-N 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-YYWVXINBSA-N DMF-d7 Substances [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 108010029144 Factor IIa Proteins 0.000 description 1
- 102000027487 Fructose-Bisphosphatase Human genes 0.000 description 1
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 229940122904 Glucagon receptor antagonist Drugs 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000990566 Homo sapiens HEAT repeat-containing protein 6 Proteins 0.000 description 1
- 101100453988 Homo sapiens KLK1 gene Proteins 0.000 description 1
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 1
- 101000801684 Homo sapiens Phospholipid-transporting ATPase ABCA1 Proteins 0.000 description 1
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 101000635804 Homo sapiens Tissue factor Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010010164 Hypertension complications Diseases 0.000 description 1
- 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 108010090444 Innovin Proteins 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 201000008450 Intracranial aneurysm Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 108010077861 Kininogens Proteins 0.000 description 1
- 102000010631 Kininogens Human genes 0.000 description 1
- 206010025282 Lymphoedema Diseases 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010027525 Microalbuminuria Diseases 0.000 description 1
- 101001050269 Mus musculus Kallikrein 1-related peptidase b1 Proteins 0.000 description 1
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101150111774 NPY5R gene Proteins 0.000 description 1
- 229910021204 NaH2 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- 102100033616 Phospholipid-transporting ATPase ABCA1 Human genes 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 206010038926 Retinopathy hypertensive Diseases 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010039286 S 2238 Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010058556 Serositis Diseases 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 206010042209 Stress Diseases 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- 101710204865 Tyrosine-protein phosphatase 1 Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 208000005707 acquired angioedema Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000024716 acute asthma Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003705 antithrombocytic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000005744 arteriovenous malformation Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229910000063 azene Inorganic materials 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 108010031969 benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- NOJMTMIRQRDZMT-GSPXQYRGSA-N bromocriptine methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 NOJMTMIRQRDZMT-GSPXQYRGSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012482 calibration solution Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 238000013132 cardiothoracic surgery Methods 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940015838 cycloset Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 238000009585 enzyme analysis Methods 0.000 description 1
- XTHPZTBDQIWSFA-UHFFFAOYSA-N ethyl 5-(difluoromethyl)-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1C(F)F XTHPZTBDQIWSFA-UHFFFAOYSA-N 0.000 description 1
- VXHCBKUFAXDEDI-UHFFFAOYSA-N ethyl 5-methoxy-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C1=CNN=C1OC VXHCBKUFAXDEDI-UHFFFAOYSA-N 0.000 description 1
- LDGZDIKIHNPBKO-UHFFFAOYSA-N ethyl 6-chloro-4-methylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)C=C1C LDGZDIKIHNPBKO-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 208000003906 hydrocephalus Diseases 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 201000001948 hypertensive retinopathy Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000002502 lymphedema Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- VKHZYWVEBNIRLX-UHFFFAOYSA-N methanesulfonohydrazide Chemical compound CS(=O)(=O)NN VKHZYWVEBNIRLX-UHFFFAOYSA-N 0.000 description 1
- VFTZKSMAJVLWOV-UHFFFAOYSA-N methyl 1h-pyrazole-4-carboxylate Chemical compound COC(=O)C=1C=NNC=1 VFTZKSMAJVLWOV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 201000011107 obstructive hydrocephalus Diseases 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000007540 photo-reduction reaction Methods 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- LQJRAJVZSIVWEN-UHFFFAOYSA-N ruthenium(2+);1,3,5-trimethylbenzene Chemical compound [Ru+2].CC1=CC(C)=CC(C)=C1 LQJRAJVZSIVWEN-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
- 208000000318 vitreous detachment Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17167549 | 2017-04-21 | ||
| ??17167549.9 | 2017-04-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201902887A true TW201902887A (zh) | 2019-01-16 |
Family
ID=58606127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW107113453A TW201902887A (zh) | 2017-04-21 | 2018-04-20 | 做為血漿激肽釋放酶抑制劑之雜芳基甲醯胺衍生物 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US10501440B2 (enExample) |
| EP (1) | EP3612523B1 (enExample) |
| JP (1) | JP7175914B2 (enExample) |
| CN (1) | CN110546146B (enExample) |
| AR (1) | AR111414A1 (enExample) |
| TW (1) | TW201902887A (enExample) |
| WO (1) | WO2018192866A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12091399B2 (en) | 2018-10-10 | 2024-09-17 | Boehringer Ingelheim International Gmbh | Phenyltetrazole derivatives as plasma kallikrein inhibitors |
| TW202144331A (zh) | 2020-02-13 | 2021-12-01 | 德商百靈佳殷格翰國際股份有限公司 | 作為血漿激肽釋放酶抑制劑之雜芳族甲醯胺衍生物 |
| TWI873290B (zh) | 2020-02-13 | 2025-02-21 | 德商百靈佳殷格翰國際股份有限公司 | 作為血漿激肽釋放酶抑制劑之雜芳族甲醯胺衍生物 |
| WO2021198534A1 (en) | 2020-04-04 | 2021-10-07 | Oxurion NV | Plasma kallikrein inhibitors for use in the treatment of coronaviral disease |
| JP7773522B2 (ja) * | 2020-07-10 | 2025-11-19 | メルク・シャープ・アンド・ドーム・エルエルシー | 血漿カリクレイン阻害薬 |
| WO2023144030A1 (en) | 2022-01-31 | 2023-08-03 | Oxurion NV | Plasma kallikrein inhibitor therapy for anti-vegf sensitization |
| WO2023148016A1 (en) | 2022-02-04 | 2023-08-10 | Oxurion NV | Biomarker for plasma kallikrein inhibitor therapy response |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103687795B (zh) | 2011-07-21 | 2016-05-11 | 蒂森克虏伯系统工程股份有限公司 | 用于在传送装置上停止和/或对准运输货物的器件和方法以及传送装置 |
| WO2013111108A1 (en) | 2012-01-27 | 2013-08-01 | Novartis Ag | 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
| ES2626968T3 (es) | 2013-05-23 | 2017-07-26 | Kalvista Pharmaceuticals Limited | Derivados heterocíclicos |
| WO2017072021A1 (en) | 2015-10-27 | 2017-05-04 | Boehringer Ingelheim International Gmbh | Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
-
2018
- 2018-04-16 CN CN201880026013.2A patent/CN110546146B/zh active Active
- 2018-04-16 WO PCT/EP2018/059633 patent/WO2018192866A1/en not_active Ceased
- 2018-04-16 US US15/953,523 patent/US10501440B2/en active Active
- 2018-04-16 JP JP2019556654A patent/JP7175914B2/ja active Active
- 2018-04-16 EP EP18719794.2A patent/EP3612523B1/en active Active
- 2018-04-20 AR ARP180101024A patent/AR111414A1/es unknown
- 2018-04-20 TW TW107113453A patent/TW201902887A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR111414A1 (es) | 2019-07-10 |
| JP7175914B2 (ja) | 2022-11-21 |
| US10501440B2 (en) | 2019-12-10 |
| WO2018192866A1 (en) | 2018-10-25 |
| EP3612523B1 (en) | 2021-06-09 |
| CN110546146B (zh) | 2023-02-21 |
| JP2020517619A (ja) | 2020-06-18 |
| CN110546146A (zh) | 2019-12-06 |
| US20180305339A1 (en) | 2018-10-25 |
| EP3612523A1 (en) | 2020-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3368524B1 (en) | Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors | |
| EP3368529B1 (en) | Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors | |
| TW201902887A (zh) | 做為血漿激肽釋放酶抑制劑之雜芳基甲醯胺衍生物 | |
| JP6828191B2 (ja) | 血漿カリクレイン阻害剤としての複素芳香族カルボキサミド誘導体 | |
| JP7703587B2 (ja) | 血漿カリクレイン阻害剤としての複素芳香族カルボキシアミド誘導体 | |
| JP7686002B2 (ja) | 血漿カリクレイン阻害剤としての複素芳香族カルボキサミド誘導体 | |
| JP2022502461A (ja) | 血漿カリクレイン阻害剤としてのフェニルテトラゾール誘導体 |