JP5587790B2 - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- JP5587790B2 JP5587790B2 JP2010541840A JP2010541840A JP5587790B2 JP 5587790 B2 JP5587790 B2 JP 5587790B2 JP 2010541840 A JP2010541840 A JP 2010541840A JP 2010541840 A JP2010541840 A JP 2010541840A JP 5587790 B2 JP5587790 B2 JP 5587790B2
- Authority
- JP
- Japan
- Prior art keywords
- furo
- benzamide
- pyrrole
- oxodihydro
- oxopentan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 218
- 239000000203 mixture Substances 0.000 claims description 307
- -1 tert- butylmethyl Chemical group 0.000 claims description 120
- 238000002360 preparation method Methods 0.000 claims description 89
- 238000000034 method Methods 0.000 claims description 85
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 48
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 48
- 102000035195 Peptidases Human genes 0.000 claims description 42
- 108091005804 Peptidases Proteins 0.000 claims description 42
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 42
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 42
- 235000019833 protease Nutrition 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 230000027455 binding Effects 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 17
- 238000003556 assay Methods 0.000 claims description 16
- 238000000338 in vitro Methods 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 208000001132 Osteoporosis Diseases 0.000 claims description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 201000008482 osteoarthritis Diseases 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000003550 marker Substances 0.000 claims description 5
- 125000002009 alkene group Chemical group 0.000 claims description 4
- 230000003993 interaction Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims description 3
- 125000002355 alkine group Chemical group 0.000 claims description 3
- 238000010171 animal model Methods 0.000 claims description 3
- 238000012875 competitive assay Methods 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000001613 neoplastic effect Effects 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 1
- BLMYFOVRPAQMPC-UHFFFAOYSA-N n-(4-methylpiperazin-1-yl)benzamide Chemical compound C1CN(C)CCN1NC(=O)C1=CC=CC=C1 BLMYFOVRPAQMPC-UHFFFAOYSA-N 0.000 claims 1
- 238000000159 protein binding assay Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 363
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 336
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 258
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 175
- 239000011734 sodium Substances 0.000 description 171
- 239000000243 solution Substances 0.000 description 167
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 148
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 138
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 137
- 235000019439 ethyl acetate Nutrition 0.000 description 132
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 87
- 239000000377 silicon dioxide Substances 0.000 description 72
- 125000003118 aryl group Chemical group 0.000 description 71
- 238000003818 flash chromatography Methods 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 61
- 239000012267 brine Substances 0.000 description 60
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 60
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 53
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 52
- 238000004128 high performance liquid chromatography Methods 0.000 description 52
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 50
- 101150065749 Churc1 gene Proteins 0.000 description 50
- 102100038239 Protein Churchill Human genes 0.000 description 50
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 50
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 50
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
- 150000002576 ketones Chemical class 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000003921 oil Substances 0.000 description 41
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
- 235000019198 oils Nutrition 0.000 description 40
- 239000007787 solid Substances 0.000 description 40
- 239000012300 argon atmosphere Substances 0.000 description 39
- 239000000725 suspension Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 37
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 37
- 239000003112 inhibitor Substances 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 239000012230 colorless oil Substances 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 34
- 239000012065 filter cake Substances 0.000 description 30
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
- 238000000746 purification Methods 0.000 description 29
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 28
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 102000004171 Cathepsin K Human genes 0.000 description 26
- 108090000625 Cathepsin K Proteins 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 229910052708 sodium Inorganic materials 0.000 description 25
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 24
- 230000008569 process Effects 0.000 description 24
- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 23
- 150000001412 amines Chemical class 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 125000002619 bicyclic group Chemical group 0.000 description 20
- 239000010949 copper Substances 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 19
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- UKHQUUMINBTTGU-UHFFFAOYSA-N bromo 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OBr)C=C1 UKHQUUMINBTTGU-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- KLDXJTOLSGUMSJ-BXKVDMCESA-N (3s,3as,6s,6as)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol Chemical compound O[C@H]1CO[C@H]2[C@@H](O)CO[C@H]21 KLDXJTOLSGUMSJ-BXKVDMCESA-N 0.000 description 17
- 150000001413 amino acids Chemical group 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 16
- 150000001336 alkenes Chemical class 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 239000007790 solid phase Substances 0.000 description 14
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 14
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 13
- 101000983944 Homo sapiens CDK2-associated and cullin domain-containing protein 1 Proteins 0.000 description 13
- 102100022241 Transmembrane protein 54 Human genes 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 230000003647 oxidation Effects 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 239000012425 OXONE® Substances 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical group CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 11
- IGLBEIJHPVVJBX-VXERAZRLSA-N [(3r,3ar,6r,6as)-3-hydroxy-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-6-yl] 4-methylbenzenesulfonate;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@H](O)[C@H]2NC1 IGLBEIJHPVVJBX-VXERAZRLSA-N 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- INTJZENRAYCATA-UHFFFAOYSA-N pyrrol-3-one Chemical compound O=C1C=CN=C1 INTJZENRAYCATA-UHFFFAOYSA-N 0.000 description 11
- JHFRMLHQIRCWEB-GMTAPVOTSA-N (3r,3as,6as)-3-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one Chemical compound O1CC(=O)[C@@H]2[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CO2 JHFRMLHQIRCWEB-GMTAPVOTSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- 150000001414 amino alcohols Chemical class 0.000 description 10
- 210000000988 bone and bone Anatomy 0.000 description 10
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 9
- 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 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 9
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 9
- 210000002997 osteoclast Anatomy 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 description 9
- 206010027476 Metastases Diseases 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
- BHRXBZFVKINLTM-DDHJBXDOSA-N [(3r,3ar,6r,6as)-3-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2[C@H](C)CO[C@@H]21 BHRXBZFVKINLTM-DDHJBXDOSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical group C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 8
- 230000009401 metastasis Effects 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 230000003389 potentiating effect Effects 0.000 description 8
- 239000012258 stirred mixture Substances 0.000 description 8
- 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 8
- WFRQSAHRHIWOQQ-SIQASLMSSA-N (3r,3ar,6s,6as)-6-bromo-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-3-ol;hydrochloride Chemical compound Cl.Br[C@H]1CN[C@@H]2[C@@H](O)CO[C@@H]21 WFRQSAHRHIWOQQ-SIQASLMSSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- WVNSZRTULFHRPK-GWOFURMSSA-N [(3r,3ar,6r,6as)-3-(difluoromethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethylsilane Chemical compound FC(F)[C@@H]1CO[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CO[C@@H]21 WVNSZRTULFHRPK-GWOFURMSSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 150000001735 carboxylic acids Chemical class 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 201000004792 malaria Diseases 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 238000010532 solid phase synthesis reaction Methods 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 239000011701 zinc Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 6
- 208000006386 Bone Resorption Diseases 0.000 description 6
- 101000761509 Homo sapiens Cathepsin K Proteins 0.000 description 6
- 208000010191 Osteitis Deformans Diseases 0.000 description 6
- 208000027868 Paget disease Diseases 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 241000223109 Trypanosoma cruzi Species 0.000 description 6
- NHTMJRNQNIYXDD-WUHRBBMRSA-N [(3r,3ar,6s,6as)-3-hydroxy-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-6-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H]1[C@H]2OC[C@H](O)[C@H]2NC1 NHTMJRNQNIYXDD-WUHRBBMRSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 150000001540 azides Chemical group 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 230000024279 bone resorption Effects 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 102000049698 human CTSK Human genes 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 208000027202 mammary Paget disease Diseases 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 6
- 238000005580 one pot reaction Methods 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- ARWTWRSURVUHRL-UHFFFAOYSA-N 2h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=CC=NC1 ARWTWRSURVUHRL-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 108090000613 Cathepsin S Proteins 0.000 description 5
- 102100035654 Cathepsin S Human genes 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 208000037147 Hypercalcaemia Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 230000008355 cartilage degradation Effects 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 150000003997 cyclic ketones Chemical class 0.000 description 5
- 238000006735 epoxidation reaction Methods 0.000 description 5
- 230000000148 hypercalcaemia Effects 0.000 description 5
- 208000030915 hypercalcemia disease Diseases 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000011345 viscous material Substances 0.000 description 5
- ZPOROQKDAPEMOL-UHFFFAOYSA-N 1h-pyrrol-3-ol Chemical compound OC=1C=CNC=1 ZPOROQKDAPEMOL-UHFFFAOYSA-N 0.000 description 4
- QPEKAAJFYLDBED-OALUTQOASA-N 2-[(1R)-1-[(2S)-2,5-dihydrofuran-2-yl]-2-(phenylmethoxycarbonylamino)ethyl]-4-methylbenzenesulfonic acid Chemical compound C(C1=CC=CC=C1)OC(=O)NC[C@H]([C@H]1OCC=C1)C1=C(C=CC(=C1)C)S(=O)(=O)O QPEKAAJFYLDBED-OALUTQOASA-N 0.000 description 4
- 241000349731 Afzelia bipindensis Species 0.000 description 4
- 206010001935 American trypanosomiasis Diseases 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- 108090000610 Cathepsin F Proteins 0.000 description 4
- 102000004176 Cathepsin F Human genes 0.000 description 4
- 108090000624 Cathepsin L Proteins 0.000 description 4
- 102000004172 Cathepsin L Human genes 0.000 description 4
- 102100026540 Cathepsin L2 Human genes 0.000 description 4
- 102000005600 Cathepsins Human genes 0.000 description 4
- 108010084457 Cathepsins Proteins 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- 101000983577 Homo sapiens Cathepsin L2 Proteins 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 4
- 240000007472 Leucaena leucocephala Species 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 108090000526 Papain Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- WVNSZRTULFHRPK-LNFKQOIKSA-N [(3s,3ar,6r,6as)-3-(difluoromethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethylsilane Chemical compound FC(F)[C@H]1CO[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CO[C@@H]21 WVNSZRTULFHRPK-LNFKQOIKSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- NNWGCBZEBGTXLV-STQMWFEESA-N benzyl n-[(2s)-2-[(2s)-2,5-dihydrofuran-2-yl]-2-hydroxyethyl]carbamate Chemical compound C([C@H](O)[C@@H]1C=CCO1)NC(=O)OCC1=CC=CC=C1 NNWGCBZEBGTXLV-STQMWFEESA-N 0.000 description 4
- PLCCQYRDWCKADT-STQMWFEESA-N benzyl n-[(2s)-2-[(2s)-2,5-dihydrofuran-2-yl]-3,3-difluoropropyl]carbamate Chemical compound C([C@H](C(F)F)[C@@H]1C=CCO1)NC(=O)OCC1=CC=CC=C1 PLCCQYRDWCKADT-STQMWFEESA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 208000024693 gingival disease Diseases 0.000 description 4
- 208000007565 gingivitis Diseases 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 229960002479 isosorbide Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 108020001756 ligand binding domains Proteins 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 150000002924 oxiranes Chemical class 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- JUHJMRCPZRWQAM-DBRKOABJSA-N (3r,3ar,6r,6ar)-3-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-ol Chemical compound O[C@@H]1CO[C@@H]2[C@H](C)CO[C@@H]21 JUHJMRCPZRWQAM-DBRKOABJSA-N 0.000 description 3
- AKFILUJFIKAZRA-XZBKPIIZSA-N (3r,3ar,6r,6ar)-6-methyl-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-3-ol Chemical compound O[C@H]1CO[C@@H]2[C@H](C)CN[C@@H]21 AKFILUJFIKAZRA-XZBKPIIZSA-N 0.000 description 3
- MDIQFLPPMDLMHR-UHFFFAOYSA-N 2,5-dihydrofuro[3,2-b]pyrrole-4-carboxylic acid Chemical compound C1C=C2C(=CCO2)N1C(=O)O MDIQFLPPMDLMHR-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- NBZRVVGXAQQXPQ-UHFFFAOYSA-N C(C)(C)C1C2C(N(C1)C(=O)OC)C(CO2)=O Chemical compound C(C)(C)C1C2C(N(C1)C(=O)OC)C(CO2)=O NBZRVVGXAQQXPQ-UHFFFAOYSA-N 0.000 description 3
- OXJVQSLZKOBIBT-UHFFFAOYSA-N CC1C2C(N(C1)C(=O)OC)C(CO2)=O Chemical compound CC1C2C(N(C1)C(=O)OC)C(CO2)=O OXJVQSLZKOBIBT-UHFFFAOYSA-N 0.000 description 3
- 108090000712 Cathepsin B Proteins 0.000 description 3
- 102000004225 Cathepsin B Human genes 0.000 description 3
- 108090000267 Cathepsin C Proteins 0.000 description 3
- 102000003902 Cathepsin C Human genes 0.000 description 3
- 208000024699 Chagas disease Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 235000019502 Orange oil Nutrition 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- GIHOYWNIYLZPEJ-PMACEKPBSA-N [(1s)-1-[(2s)-2,5-dihydrofuran-2-yl]-2-(phenylmethoxycarbonylamino)ethyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]([C@@H]1C=CCO1)CNC(=O)OCC1=CC=CC=C1 GIHOYWNIYLZPEJ-PMACEKPBSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940019748 antifibrinolytic proteinase inhibitors Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- ZRJVZQGXZQVFKQ-XQHKEYJVSA-N benzyl N-[(2R)-2-[(1R,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl]-3,3-difluoropropyl]carbamate Chemical compound C([C@@H](C(F)F)[C@@H]1[C@H]2O[C@H]2CO1)NC(=O)OCC1=CC=CC=C1 ZRJVZQGXZQVFKQ-XQHKEYJVSA-N 0.000 description 3
- PLCCQYRDWCKADT-OLZOCXBDSA-N benzyl N-[(2R)-2-[(2S)-2,5-dihydrofuran-2-yl]-3,3-difluoropropyl]carbamate Chemical compound C([C@@H](C(F)F)[C@@H]1C=CCO1)NC(=O)OCC1=CC=CC=C1 PLCCQYRDWCKADT-OLZOCXBDSA-N 0.000 description 3
- ZRJVZQGXZQVFKQ-RVMXOQNASA-N benzyl n-[(2s)-2-[(1r,2r,5s)-3,6-dioxabicyclo[3.1.0]hexan-2-yl]-3,3-difluoropropyl]carbamate Chemical compound C([C@H](C(F)F)[C@@H]1[C@H]2O[C@H]2CO1)NC(=O)OCC1=CC=CC=C1 ZRJVZQGXZQVFKQ-RVMXOQNASA-N 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- RYEXTBOQKFUPOE-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].CC[CH2-] RYEXTBOQKFUPOE-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 239000010502 orange oil Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000019834 papain Nutrition 0.000 description 3
- 229940055729 papain Drugs 0.000 description 3
- 230000003071 parasitic effect Effects 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 201000001245 periodontitis Diseases 0.000 description 3
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- 235000010487 tragacanth Nutrition 0.000 description 3
- 239000000196 tragacanth Substances 0.000 description 3
- 229940116362 tragacanth Drugs 0.000 description 3
- 238000010200 validation analysis Methods 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- ABBSKLJPIIRFMR-SECBINFHSA-N (2s)-2-(1-methylcyclopentyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C1(C)CCCC1 ABBSKLJPIIRFMR-SECBINFHSA-N 0.000 description 2
- BTQSWRBSXLFCPG-ZCFIWIBFSA-N (2s)-2-amino-2-(1-methylcyclopentyl)acetic acid Chemical compound OC(=O)[C@@H](N)C1(C)CCCC1 BTQSWRBSXLFCPG-ZCFIWIBFSA-N 0.000 description 2
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 description 2
- HOLSXKBDPCXTPO-HNNXBMFYSA-N (4s)-4-benzyl-3-[2-(1-methylcyclopentyl)acetyl]-1,3-oxazolidin-2-one Chemical compound C([C@@H]1CC=2C=CC=CC=2)OC(=O)N1C(=O)CC1(C)CCCC1 HOLSXKBDPCXTPO-HNNXBMFYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- AEMWUHCKKDPRSK-UHFFFAOYSA-N (ne)-n-diazo-2,4,6-tri(propan-2-yl)benzenesulfonamide Chemical compound CC(C)C1=CC(C(C)C)=C(S(=O)(=O)N=[N+]=[N-])C(C(C)C)=C1 AEMWUHCKKDPRSK-UHFFFAOYSA-N 0.000 description 2
- QBVHMPFSDVNFAY-UHFFFAOYSA-N 1,1,1-trifluorobutan-2-one Chemical compound CCC(=O)C(F)(F)F QBVHMPFSDVNFAY-UHFFFAOYSA-N 0.000 description 2
- MNIBBVOEXUQHFF-UHFFFAOYSA-N 1-methylcyclopentanecarboxylic acid Chemical compound OC(=O)C1(C)CCCC1 MNIBBVOEXUQHFF-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- ZHQAIBYWBFMHHQ-UHFFFAOYSA-N 2-(1-methylcyclopentyl)acetic acid Chemical compound OC(=O)CC1(C)CCCC1 ZHQAIBYWBFMHHQ-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OIEAXXWLLCWXTO-UHFFFAOYSA-N 4,5,6,6a-tetrahydro-3ah-furo[3,2-b]pyrrol-3-one Chemical compound C1CNC2C(=O)COC21 OIEAXXWLLCWXTO-UHFFFAOYSA-N 0.000 description 2
- MDUZYUPCNVOIEG-UHFFFAOYSA-N 4-(2-piperidin-4-yl-1,3-thiazol-4-yl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(C2CCNCC2)=N1 MDUZYUPCNVOIEG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IZOOJDDPLCBCCJ-UHFFFAOYSA-N 4-[5-methyl-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC(=CC=2)C(O)=O)=C(C)S1 IZOOJDDPLCBCCJ-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Chemical compound OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- PKIIPQWNTCDRHX-UHFFFAOYSA-N C(C)C1C2C(N(C1)C(=O)OC)C(CO2)=O Chemical compound C(C)C1C2C(N(C1)C(=O)OC)C(CO2)=O PKIIPQWNTCDRHX-UHFFFAOYSA-N 0.000 description 2
- KKVSHHTXCIOQTC-UHFFFAOYSA-N C(C)C1C2C(N(C1)C(=O)OC)C(CO2)O Chemical compound C(C)C1C2C(N(C1)C(=O)OC)C(CO2)O KKVSHHTXCIOQTC-UHFFFAOYSA-N 0.000 description 2
- NOXHOJAXBQRNEY-UHFFFAOYSA-N C1(=CC=C(C=C1)S(=O)(=O)O)C.C1(=CC=C(C=C1)S(=O)(=O)O)C.CO Chemical compound C1(=CC=C(C=C1)S(=O)(=O)O)C.C1(=CC=C(C=C1)S(=O)(=O)O)C.CO NOXHOJAXBQRNEY-UHFFFAOYSA-N 0.000 description 2
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 2
- 208000000094 Chronic Pain 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
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 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 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- WPKVODVZLLOILV-UHFFFAOYSA-N OC1COC2C1N(CC2C(C)C)C(=O)OC Chemical compound OC1COC2C1N(CC2C(C)C)C(=O)OC WPKVODVZLLOILV-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 241000233872 Pneumocystis carinii Species 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 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 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- JIJCDBITGHDTDP-STQMWFEESA-N [(1s)-1-[(2s)-2,5-dihydrofuran-2-yl]-2-hydroxyethyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H](CO)[C@@H]1C=CCO1 JIJCDBITGHDTDP-STQMWFEESA-N 0.000 description 2
- JJVVXLOFAKFSFP-SFYZADRCSA-N [(2r)-2-[(2s)-2,5-dihydrofuran-2-yl]propyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](C)[C@H]1OCC=C1 JJVVXLOFAKFSFP-SFYZADRCSA-N 0.000 description 2
- FGJZRMSVFCYGGE-FDYHWXHSSA-N [(3r,3ar,6r,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@@H](O)[C@H]2OC1 FGJZRMSVFCYGGE-FDYHWXHSSA-N 0.000 description 2
- SXUKLLWDFDRBHA-IJLUTSLNSA-N [(3r,3as,6ar)-6-methylidene-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3-yl]oxy-tert-butyl-dimethylsilane Chemical compound O1CC(=C)[C@@H]2[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CO2 SXUKLLWDFDRBHA-IJLUTSLNSA-N 0.000 description 2
- LYUMSFVURGTNGM-UMSGYPCISA-N [(3r,3as,6s,6as)-6-bromo-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@H](Br)[C@H]2OC1 LYUMSFVURGTNGM-UMSGYPCISA-N 0.000 description 2
- LFXDGKWHPSDRCT-IYWMVGAKSA-N [(3s,3as,6r,6as)-6-(4-methylphenyl)sulfonyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@H](OS(=O)(=O)C=3C=CC(C)=CC=3)[C@H]2OC1 LFXDGKWHPSDRCT-IYWMVGAKSA-N 0.000 description 2
- LYUMSFVURGTNGM-WUHRBBMRSA-N [(3s,3as,6s,6as)-6-bromo-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H]1[C@H]2OC[C@H](Br)[C@H]2OC1 LYUMSFVURGTNGM-WUHRBBMRSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- QDQQNFFWHWPMJZ-YXCITZCRSA-N benzyl (3r,3ar,6r,6ar)-3-hydroxy-6-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@H]([C@H]1OC[C@H](O)[C@H]11)C)N1C(=O)OCC1=CC=CC=C1 QDQQNFFWHWPMJZ-YXCITZCRSA-N 0.000 description 2
- QDQQNFFWHWPMJZ-SCUASFONSA-N benzyl (3r,3ar,6s,6ar)-3-hydroxy-6-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@@H]([C@H]1OC[C@H](O)[C@H]11)C)N1C(=O)OCC1=CC=CC=C1 QDQQNFFWHWPMJZ-SCUASFONSA-N 0.000 description 2
- NNWGCBZEBGTXLV-OLZOCXBDSA-N benzyl n-[(2r)-2-[(2s)-2,5-dihydrofuran-2-yl]-2-hydroxyethyl]carbamate Chemical compound C([C@@H](O)[C@@H]1C=CCO1)NC(=O)OCC1=CC=CC=C1 NNWGCBZEBGTXLV-OLZOCXBDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- AZSZCFSOHXEJQE-UHFFFAOYSA-N dibromodifluoromethane Chemical compound FC(F)(Br)Br AZSZCFSOHXEJQE-UHFFFAOYSA-N 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical class O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 108010007459 falcipain Proteins 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000003106 haloaryl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- KQZUSJUULLDTNM-UHFFFAOYSA-N methyl 6-(difluoromethyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound FC(C1C2C(N(C1)C(=O)OC)C(CO2)=O)F KQZUSJUULLDTNM-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 201000000585 muscular atrophy Diseases 0.000 description 2
- 201000006938 muscular dystrophy Diseases 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 201000004409 schistosomiasis Diseases 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 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
- 239000003381 stabilizer Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 125000005490 tosylate group Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- ULDOPPAZCQXBOZ-RITPCOANSA-N (1r)-2-amino-1-[(2s)-2,5-dihydrofuran-2-yl]ethanol Chemical compound NC[C@@H](O)[C@H]1OCC=C1 ULDOPPAZCQXBOZ-RITPCOANSA-N 0.000 description 1
- ULDOPPAZCQXBOZ-WDSKDSINSA-N (1s)-2-amino-1-[(2s)-2,5-dihydrofuran-2-yl]ethanol Chemical compound NC[C@H](O)[C@H]1OCC=C1 ULDOPPAZCQXBOZ-WDSKDSINSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- WLNNYKMTYVPSDL-VYDKEIKOSA-N (2S)-2-(1-carboxyethylamino)-4-[[(1R)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]butanoic acid Chemical compound CC(N[C@@H](CCN[C@H](Cc1cnc[nH]1)C(O)=O)C(O)=O)C(O)=O WLNNYKMTYVPSDL-VYDKEIKOSA-N 0.000 description 1
- MJCYCIDKRVXENY-RQJHMYQMSA-N (2r)-2-[(2s)-2,5-dihydrofuran-2-yl]propan-1-amine Chemical compound NC[C@@H](C)[C@H]1OCC=C1 MJCYCIDKRVXENY-RQJHMYQMSA-N 0.000 description 1
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 description 1
- LPBSHGLDBQBSPI-YFKPBYRVSA-N (2s)-2-amino-4,4-dimethylpentanoic acid Chemical compound CC(C)(C)C[C@H](N)C(O)=O LPBSHGLDBQBSPI-YFKPBYRVSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- LPUZUWVJKQBGRM-BQBZGAKWSA-N (3S)-3-[(2S)-2,5-dihydrofuran-2-yl]-4,4-difluorobutane-1-sulfonic acid Chemical compound C1C=C[C@H](O1)[C@H](CCS(=O)(=O)O)C(F)F LPUZUWVJKQBGRM-BQBZGAKWSA-N 0.000 description 1
- KKLSNZQQTFJYMJ-ULAWRXDQSA-N (3r,3ar,6r,6ar)-6-ethyl-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-3-ol Chemical compound O[C@H]1CO[C@@H]2[C@H](CC)CN[C@@H]21 KKLSNZQQTFJYMJ-ULAWRXDQSA-N 0.000 description 1
- AKDSNJPFRALERM-GWOFURMSSA-N (3r,3ar,6r,6as)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol Chemical compound O[C@@H]1CO[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CO[C@@H]21 AKDSNJPFRALERM-GWOFURMSSA-N 0.000 description 1
- AKFILUJFIKAZRA-VWDOSNQTSA-N (3r,3ar,6s,6ar)-6-methyl-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-3-ol Chemical compound O[C@H]1CO[C@@H]2[C@@H](C)CN[C@@H]21 AKFILUJFIKAZRA-VWDOSNQTSA-N 0.000 description 1
- WBLGQLRFJPEGBA-XZBKPIIZSA-N (3r,3ar,6s,6as)-6-bromo-3-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound Br[C@H]1CO[C@@H]2[C@H](C)CO[C@@H]21 WBLGQLRFJPEGBA-XZBKPIIZSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical group CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 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
- 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 1
- LRHRHAWNXCGABU-UHFFFAOYSA-N 2-(cyclopentylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCC1 LRHRHAWNXCGABU-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- FSAKEOSTPLGOMZ-UHFFFAOYSA-N 3-methyl-4-[5-(morpholin-4-ylmethyl)furan-2-yl]benzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1C(O1)=CC=C1CN1CCOCC1 FSAKEOSTPLGOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- UXURPZISNQQAOY-UHFFFAOYSA-N 4-(2-morpholin-4-yl-1,3-thiazol-4-yl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(N2CCOCC2)=N1 UXURPZISNQQAOY-UHFFFAOYSA-N 0.000 description 1
- MDYHBLVQVAEYCU-UHFFFAOYSA-N 4-(2-piperidin-1-yl-1,3-thiazol-4-yl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(N2CCCCC2)=N1 MDYHBLVQVAEYCU-UHFFFAOYSA-N 0.000 description 1
- WNHYUHFPZOYTOQ-UHFFFAOYSA-N 4-(6-morpholin-4-ylpyridin-2-yl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC(N2CCOCC2)=N1 WNHYUHFPZOYTOQ-UHFFFAOYSA-N 0.000 description 1
- BZISXKHFQYSYGO-UHFFFAOYSA-N 4-[(hydrazinecarbonylamino)methyl]cyclohexane-1-carboxylic acid Chemical compound NNC(=O)NCC1CCC(C(O)=O)CC1 BZISXKHFQYSYGO-UHFFFAOYSA-N 0.000 description 1
- LSQFTCHHVMCXMO-UHFFFAOYSA-N 4-[(hydrazinecarbonylamino)methyl]cyclohexane-1-carboxylic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NNC(=O)NCC1CCC(C(O)=O)CC1 LSQFTCHHVMCXMO-UHFFFAOYSA-N 0.000 description 1
- YWFGLSUBMHQMHT-UHFFFAOYSA-N 4-[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1CN(C)CCC1C1=NC(C=2C=CC(=CC=2)C(O)=O)=CS1 YWFGLSUBMHQMHT-UHFFFAOYSA-N 0.000 description 1
- MHBXDKHZXZWGMJ-UHFFFAOYSA-N 4-[2-(1-methylpyrrolidin-3-yl)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1N(C)CCC1C1=NC(C=2C=CC(=CC=2)C(O)=O)=CS1 MHBXDKHZXZWGMJ-UHFFFAOYSA-N 0.000 description 1
- MHYCYTQPROXDDO-UHFFFAOYSA-N 4-[2-(4-fluoro-1-methylpyrrolidin-2-yl)-1,3-thiazol-4-yl]benzoic acid Chemical compound CN1CC(F)CC1C1=NC(C=2C=CC(=CC=2)C(O)=O)=CS1 MHYCYTQPROXDDO-UHFFFAOYSA-N 0.000 description 1
- NPHPALJCGYEBNO-UHFFFAOYSA-N 4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC(=CC=2)C(O)=O)=CS1 NPHPALJCGYEBNO-UHFFFAOYSA-N 0.000 description 1
- CDLPKMYUMTVESV-UHFFFAOYSA-N 4-[2-(cyclopentylamino)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(NC2CCCC2)=N1 CDLPKMYUMTVESV-UHFFFAOYSA-N 0.000 description 1
- OZGWAUMFNXAOJA-UHFFFAOYSA-N 4-[2-(cyclopropylamino)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(NC2CC2)=N1 OZGWAUMFNXAOJA-UHFFFAOYSA-N 0.000 description 1
- NTIQEIBVHYHHHA-UHFFFAOYSA-N 4-[2-(methylamino)-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C(NC)=NC(C=2C=CC(=CC=2)C(O)=O)=C1 NTIQEIBVHYHHHA-UHFFFAOYSA-N 0.000 description 1
- UWHYXOJCLVNNEX-UHFFFAOYSA-N 4-[2-(propan-2-ylamino)-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C(NC(C)C)=NC(C=2C=CC(=CC=2)C(O)=O)=C1 UWHYXOJCLVNNEX-UHFFFAOYSA-N 0.000 description 1
- TXBSXYCYUANELM-UHFFFAOYSA-N 4-[2-(pyridin-3-ylamino)-1,3-thiazol-4-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CSC(NC=2C=NC=CC=2)=N1 TXBSXYCYUANELM-UHFFFAOYSA-N 0.000 description 1
- SCDWMEZPRJGJCF-VIFPVBQESA-N 4-[2-[(1s)-1-(dimethylamino)ethyl]-5-methyl-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C([C@@H](N(C)C)C)=NC(C=2C=CC(=CC=2)C(O)=O)=C1C SCDWMEZPRJGJCF-VIFPVBQESA-N 0.000 description 1
- CZZRCOLWDDHVSV-QMMMGPOBSA-N 4-[2-[(1s)-1-(methylamino)ethyl]-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C([C@H](C)NC)=NC(C=2C=CC(=CC=2)C(O)=O)=C1 CZZRCOLWDDHVSV-QMMMGPOBSA-N 0.000 description 1
- VVWFBFSTKITEHY-QMMMGPOBSA-N 4-[2-[(1s)-1-(methylamino)ethyl]-1,3-thiazol-5-yl]benzoic acid Chemical compound S1C([C@H](C)NC)=NC=C1C1=CC=C(C(O)=O)C=C1 VVWFBFSTKITEHY-QMMMGPOBSA-N 0.000 description 1
- AECPLWYYFCBDJC-UHFFFAOYSA-N 4-[2-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-thiazol-4-yl]benzoic acid Chemical compound C1CN(CCOC)CCN1C1=NC(C=2C=CC(=CC=2)C(O)=O)=CS1 AECPLWYYFCBDJC-UHFFFAOYSA-N 0.000 description 1
- FVNVHWPPSBKOFV-UHFFFAOYSA-N 4-[2-[cyclopropyl(methyl)amino]-1,3-thiazol-4-yl]benzoic acid Chemical compound N=1C(C=2C=CC(=CC=2)C(O)=O)=CSC=1N(C)C1CC1 FVNVHWPPSBKOFV-UHFFFAOYSA-N 0.000 description 1
- APWVCIPMLSCOSA-UHFFFAOYSA-N 4-[5-(1-morpholin-4-ylethyl)furan-2-yl]benzoic acid Chemical compound C=1C=C(C=2C=CC(=CC=2)C(O)=O)OC=1C(C)N1CCOCC1 APWVCIPMLSCOSA-UHFFFAOYSA-N 0.000 description 1
- ASSAUKKHOJBYBA-UHFFFAOYSA-N 4-[5-(1-morpholin-4-ylethyl)thiophen-2-yl]benzoic acid Chemical compound C=1C=C(C=2C=CC(=CC=2)C(O)=O)SC=1C(C)N1CCOCC1 ASSAUKKHOJBYBA-UHFFFAOYSA-N 0.000 description 1
- RURWDXPORIRGJQ-UHFFFAOYSA-N 4-[5-(morpholin-4-ylmethyl)thiophen-2-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(S1)=CC=C1CN1CCOCC1 RURWDXPORIRGJQ-UHFFFAOYSA-N 0.000 description 1
- RUDWQYUJJINAIS-UHFFFAOYSA-N 4-[5-(piperidin-1-ylmethyl)thiophen-2-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(S1)=CC=C1CN1CCCCC1 RUDWQYUJJINAIS-UHFFFAOYSA-N 0.000 description 1
- WQMUPPRNGBLJAL-QMMMGPOBSA-N 4-[5-methyl-2-[(1s)-1-(methylamino)ethyl]-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C([C@H](C)NC)=NC(C=2C=CC(=CC=2)C(O)=O)=C1C WQMUPPRNGBLJAL-QMMMGPOBSA-N 0.000 description 1
- XIMDIKHMVTVUNL-UHFFFAOYSA-N 4-[5-methyl-2-[methyl(propan-2-yl)amino]-1,3-thiazol-4-yl]benzoic acid Chemical compound S1C(N(C)C(C)C)=NC(C=2C=CC(=CC=2)C(O)=O)=C1C XIMDIKHMVTVUNL-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- QTQCQAKKBLFCMA-UHFFFAOYSA-N 4H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate Chemical compound O1C=CC=2NC=C(C21)OS(=O)(=O)C2=CC=C(C=C2)C QTQCQAKKBLFCMA-UHFFFAOYSA-N 0.000 description 1
- BGGNGMKTBJILKC-UHFFFAOYSA-N 4h-furo[3,2-b]pyrrol-3-ol Chemical compound C1=CNC2=C1OC=C2O BGGNGMKTBJILKC-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- JVKKJAYKGOKMIB-IJXRJRJASA-N 9h-fluoren-9-ylmethyl (3r,3ar,6s,6ar)-6-(difluoromethyl)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N1C[C@H](C(F)F)[C@H]2OC[C@H](O)[C@@H]12 JVKKJAYKGOKMIB-IJXRJRJASA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 101150034980 BRDT gene Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- VYFFKKRVYNYLRZ-LNTIDCRLSA-N C[C@H]1[C@H](NC(=O)C(=N/OC(C)(C)C(C)=O)\C2=CSC(N)=N2)C(=O)N1S(O)(=O)=O Chemical compound C[C@H]1[C@H](NC(=O)C(=N/OC(C)(C)C(C)=O)\C2=CSC(N)=N2)C(=O)N1S(O)(=O)=O VYFFKKRVYNYLRZ-LNTIDCRLSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 240000006432 Carica papaya Species 0.000 description 1
- 235000009467 Carica papaya Nutrition 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- NIYLDIPHWCDBFJ-VJABJLATSA-N Cl.O[C@H]1CO[C@@H]2[C@@H]1NC[C@H]2CC2=C(C=CC=C2)S(=O)(=O)O Chemical compound Cl.O[C@H]1CO[C@@H]2[C@@H]1NC[C@H]2CC2=C(C=CC=C2)S(=O)(=O)O NIYLDIPHWCDBFJ-VJABJLATSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000222716 Crithidia Species 0.000 description 1
- 229910017489 Cu I Inorganic materials 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical class NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- 102000016921 Integrin-Binding Sialoprotein Human genes 0.000 description 1
- 108010028750 Integrin-Binding Sialoprotein Proteins 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 241000222734 Leishmania mexicana Species 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 201000011442 Metachromatic leukodystrophy Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- CXGBZWWFLSWUGZ-UHFFFAOYSA-N OC1COC2C1N(CC2C)C(=O)OC Chemical compound OC1COC2C1N(CC2C)C(=O)OC CXGBZWWFLSWUGZ-UHFFFAOYSA-N 0.000 description 1
- BINUNELUYLGICO-UHFFFAOYSA-N OC1COC2C1N(CC2CCC)C(=O)OC Chemical compound OC1COC2C1N(CC2CCC)C(=O)OC BINUNELUYLGICO-UHFFFAOYSA-N 0.000 description 1
- KKFLFCXVJVUNQC-RVMXOQNASA-N O[C@H]1CO[C@@H]2[C@@H]1NC[C@H]2C2=CC=C(C=C2)C Chemical compound O[C@H]1CO[C@@H]2[C@@H]1NC[C@H]2C2=CC=C(C=C2)C KKFLFCXVJVUNQC-RVMXOQNASA-N 0.000 description 1
- MEGHBXXHSYOCGX-WUHRBBMRSA-N O[C@H]1CO[C@@H]2[C@H](CN([C@H]12)C(=O)OCc1ccccc1)C(F)F Chemical compound O[C@H]1CO[C@@H]2[C@H](CN([C@H]12)C(=O)OCc1ccccc1)C(F)F MEGHBXXHSYOCGX-WUHRBBMRSA-N 0.000 description 1
- 102000004067 Osteocalcin Human genes 0.000 description 1
- 108090000573 Osteocalcin Proteins 0.000 description 1
- 102000009890 Osteonectin Human genes 0.000 description 1
- 108010077077 Osteonectin Proteins 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241000223829 Plasmodium vinckei Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- JIJCDBITGHDTDP-QWHCGFSZSA-N [(1r)-1-[(2s)-2,5-dihydrofuran-2-yl]-2-hydroxyethyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H](CO)[C@@H]1C=CCO1 JIJCDBITGHDTDP-QWHCGFSZSA-N 0.000 description 1
- OVKSSSQHNQGYRU-RQJHMYQMSA-N [(2r)-2-[(2s)-2,5-dihydrofuran-2-yl]-3,3-difluoropropyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](C(F)F)[C@H]1OCC=C1 OVKSSSQHNQGYRU-RQJHMYQMSA-N 0.000 description 1
- NHTMJRNQNIYXDD-UMSGYPCISA-N [(3r,3ar,6r,6as)-3-hydroxy-3,3a,4,5,6,6a-hexahydro-2h-furo[3,2-b]pyrrol-6-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@H](O)[C@H]2NC1 NHTMJRNQNIYXDD-UMSGYPCISA-N 0.000 description 1
- XDPLWQFWMBKRLM-FMKGYKFTSA-N [(3r,3ar,6r,6as)-3-methyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 4-methylbenzenesulfonate Chemical compound O([C@H]1[C@H]2OC[C@H]([C@H]2OC1)C)S(=O)(=O)C1=CC=C(C)C=C1 XDPLWQFWMBKRLM-FMKGYKFTSA-N 0.000 description 1
- RAZAUWFFZMGKRQ-GMTAPVOTSA-N [(3r,3as,6ar)-6-(difluoromethylidene)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3-yl]oxy-tert-butyl-dimethylsilane Chemical compound O1CC(=C(F)F)[C@@H]2[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CO2 RAZAUWFFZMGKRQ-GMTAPVOTSA-N 0.000 description 1
- LFXDGKWHPSDRCT-UAFMIMERSA-N [(3r,3as,6r,6as)-6-(4-methylphenyl)sulfonyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@@H](OS(=O)(=O)C=3C=CC(C)=CC=3)[C@H]2OC1 LFXDGKWHPSDRCT-UAFMIMERSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001265 acyl fluorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000007924 bacterial virulence factor Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- DCHKNJYQVKKZJP-CAOSSQGBSA-N benzyl (3r,3ar,6r,6ar)-3-hydroxy-6-propan-2-yl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@H]([C@H]1OC[C@H](O)[C@H]11)C(C)C)N1C(=O)OCC1=CC=CC=C1 DCHKNJYQVKKZJP-CAOSSQGBSA-N 0.000 description 1
- MEGHBXXHSYOCGX-YVECIDJPSA-N benzyl (3r,3ar,6r,6ar)-6-(difluoromethyl)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@H]([C@H]1OC[C@@H]([C@@H]21)O)C(F)F)N2C(=O)OCC1=CC=CC=C1 MEGHBXXHSYOCGX-YVECIDJPSA-N 0.000 description 1
- UNYYLQIFVBWUSD-LXTVHRRPSA-N benzyl (3r,3ar,6r,6ar)-6-ethyl-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@H]([C@H]1OC[C@H](O)[C@H]11)CC)N1C(=O)OCC1=CC=CC=C1 UNYYLQIFVBWUSD-LXTVHRRPSA-N 0.000 description 1
- DCHKNJYQVKKZJP-QKPAOTATSA-N benzyl (3r,3ar,6s,6ar)-3-hydroxy-6-propan-2-yl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@@H]([C@H]1OC[C@H](O)[C@H]11)C(C)C)N1C(=O)OCC1=CC=CC=C1 DCHKNJYQVKKZJP-QKPAOTATSA-N 0.000 description 1
- IHBUHWQPFDYFFO-CAOSSQGBSA-N benzyl (3r,3ar,6s,6ar)-3-hydroxy-6-propyl-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@@H]([C@H]1OC[C@H](O)[C@H]11)CCC)N1C(=O)OCC1=CC=CC=C1 IHBUHWQPFDYFFO-CAOSSQGBSA-N 0.000 description 1
- GWNUAHSLBFDRIB-QKPAOTATSA-N benzyl (3r,3ar,6s,6ar)-6-cyclopropyl-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@@H]([C@H]1OC[C@@H]([C@@H]21)O)C1CC1)N2C(=O)OCC1=CC=CC=C1 GWNUAHSLBFDRIB-QKPAOTATSA-N 0.000 description 1
- UNYYLQIFVBWUSD-BYNSBNAKSA-N benzyl (3r,3ar,6s,6ar)-6-ethyl-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C([C@@H]([C@H]1OC[C@H](O)[C@H]11)CC)N1C(=O)OCC1=CC=CC=C1 UNYYLQIFVBWUSD-BYNSBNAKSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood 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
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 239000013000 chemical inhibitor Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 108090000711 cruzipain Proteins 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000007878 drug screening assay Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005837 enolization reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YUCFVHQCAFKDQG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH] YUCFVHQCAFKDQG-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910001853 inorganic hydroxide Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001361 intraarterial 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
- 238000010253 intravenous injection Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000003458 metachromatic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-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
- 230000003228 microsomal effect Effects 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 210000005088 multinucleated cell Anatomy 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- BWYBBMQLUKXECQ-GIVPXCGWSA-N n-[(2s)-4-methyl-1-[[(4s,7r)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide Chemical compound N1([C@H](C)CC[C@@H](C(C1)=O)NC(=O)[C@@H](NC(=O)C=1OC2=CC=CC=C2C=1)CC(C)C)S(=O)(=O)C1=CC=CC=N1 BWYBBMQLUKXECQ-GIVPXCGWSA-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
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical group C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 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
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003349 osteoarthritic effect Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- FHHJDRFHHWUPDG-UHFFFAOYSA-N peroxysulfuric acid Chemical compound OOS(O)(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229950002818 relacatib Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 125000003198 secondary alcohol group Chemical group 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- HZSZXHFOOIAHBV-ZJIFWQFVSA-N tert-butyl (3r,3ar,6r,6as)-3-hydroxy-6-(4-methylphenyl)sulfonyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1[C@H]2OC[C@H](O)[C@H]2N(C(=O)OC(C)(C)C)C1 HZSZXHFOOIAHBV-ZJIFWQFVSA-N 0.000 description 1
- OEHCMIRKCABPBR-RBXMUDONSA-N tert-butyl (3r,3ar,6s,6as)-6-bromo-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole-4-carboxylate Chemical compound O1C[C@H](O)[C@H]2N(C(=O)OC(C)(C)C)C[C@H](Br)[C@H]21 OEHCMIRKCABPBR-RBXMUDONSA-N 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
- 238000011200 topical administration Methods 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
- 238000012546 transfer Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 238000012070 whole genome sequencing analysis Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Neurosurgery (AREA)
- Virology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0800338.6 | 2008-01-09 | ||
| GB0800338A GB0800338D0 (en) | 2008-01-09 | 2008-01-09 | Compounds |
| GB0808669.6 | 2008-05-13 | ||
| GB0808669A GB0808669D0 (en) | 2008-05-13 | 2008-05-13 | Compounds |
| PCT/GB2009/000039 WO2009087379A2 (en) | 2008-01-09 | 2009-01-07 | Tetrahydrofuro (3, 2 -b) pyrrol- 3 -one derivatives as inhibitors of cysteine proteinases |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2011509282A JP2011509282A (ja) | 2011-03-24 |
| JP2011509282A5 JP2011509282A5 (https=) | 2012-02-23 |
| JP5587790B2 true JP5587790B2 (ja) | 2014-09-10 |
Family
ID=40791443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010541840A Expired - Fee Related JP5587790B2 (ja) | 2008-01-09 | 2009-01-07 | 化合物 |
Country Status (4)
| Country | Link |
|---|---|
| US (3) | US8501744B2 (https=) |
| EP (2) | EP2719700A1 (https=) |
| JP (1) | JP5587790B2 (https=) |
| WO (1) | WO2009087379A2 (https=) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU581929B2 (en) * | 1985-09-16 | 1989-03-09 | Schering Corporation | Antihypertensive agents, pharmaceutical compositions containing them and processes for the preparation of the agents and compositions |
| GB0817424D0 (en) | 2008-09-24 | 2008-10-29 | Medivir Ab | Protease inhibitors |
| AU2013305759C1 (en) | 2012-08-23 | 2018-01-18 | Janssen Biopharma, Inc. | Compounds for the treatment of paramoxyvirus viral infections |
| WO2014111465A1 (en) | 2013-01-17 | 2014-07-24 | Sanofi | Isomannide derivatives as inhibitors of soluble epoxide hydrolase |
| NZ716822A (en) * | 2013-08-21 | 2017-10-27 | Alios Biopharma Inc | Antiviral compounds |
| WO2015038655A1 (en) | 2013-09-12 | 2015-03-19 | Alios Biopharma, Inc. | Aza-pyridone compounds and uses thereof |
| MA41614A (fr) | 2015-02-25 | 2018-01-02 | Alios Biopharma Inc | Composés antiviraux |
| GB201506658D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
| GB201506660D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
Family Cites Families (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3444216A (en) | 1966-11-16 | 1969-05-13 | Upjohn Co | Process for the oxidation of primary and secondary alcohols |
| NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
| US5128448A (en) | 1990-01-10 | 1992-07-07 | Hoffman-La Roche Inc. | CCK analogs with appetite regulating activity |
| US5374623A (en) | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
| CA2111930A1 (en) | 1992-12-25 | 1994-06-26 | Ryoichi Ando | Aminoketone derivatives |
| DZ2285A1 (fr) | 1996-08-08 | 2002-12-25 | Smithkline Beecham Corp | Inhibiteurs de protéase de la cystéine. |
| US6043218A (en) | 1996-10-22 | 2000-03-28 | Medical University Of South Carolina | Positively charged non-natural amino acids, methods of making thereof, and use thereof in peptides |
| AR013079A1 (es) | 1997-05-06 | 2000-12-13 | Smithkline Beecham Corp | Derivados sustituidos de tetrahidrofurano-3-onas, de tetrahidropirano-3- onas y tetrahidrotiofen-3-onas, un procedimiento para su preparacion unacomposicion farmaceutica de un medicamento util como inhibidores de proteasas e intermediarios |
| TR200001189T2 (tr) | 1997-11-05 | 2000-09-21 | Novartis Ag. | Dipeptid nitriller. |
| GB9806287D0 (en) | 1998-03-24 | 1998-05-20 | Synphar Lab Inc | Monobactam enzyme inhibitors |
| MA26618A1 (fr) | 1998-04-09 | 2004-12-20 | Smithkline Beecham Corp | Composes et compositions pharmaceutiques pour le traitement du paludisme |
| DZ2815A1 (fr) | 1998-06-12 | 2003-12-01 | Smithkline Beecham Corp | Inhibiteurs de protéase. |
| JP2003527819A (ja) | 1998-08-14 | 2003-09-24 | スミスクライン・ビーチャム・コーポレイション | カテプシンｋの阻害方法 |
| ES2142773B1 (es) | 1998-10-07 | 2001-01-01 | Lacer Sa | Derivados de mononitrato de isosorbida y su empleo como agentes vasodilatadores con tolerancia desminuida. |
| CO5150165A1 (es) | 1998-11-13 | 2002-04-29 | Smithkline Beecham Plc | Inhibidores de proteasa: tipo catepsina k |
| EP1155010A1 (en) | 1999-02-20 | 2001-11-21 | AstraZeneca AB | Acetamido acetonitrile derivatives as inhibitors of cathepsin l and/or cathepsin s |
| AU2560000A (en) | 1999-02-20 | 2000-09-04 | Astrazeneca Ab | Di- and tripeptide nitrile derivatives as inhibitors of cathepsin l and cathepsin |
| GB9903861D0 (en) | 1999-02-20 | 1999-04-14 | Zeneca Ltd | Chemical compounds |
| WO2000051998A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| TW200404789A (en) | 1999-03-15 | 2004-04-01 | Axys Pharm Inc | Novel compounds and compositions as protease inhibitors |
| HK1039110A1 (zh) | 1999-03-15 | 2002-04-12 | Axys Pharmaceuticals, Inc. | 以新颖的合成物及组分作为蛋白酶抑制剂 |
| CN1362947A (zh) | 1999-03-15 | 2002-08-07 | Axys药物公司 | 用作蛋白酶抑制剂的n－氰基甲基酰胺 |
| GB9907683D0 (en) | 1999-04-06 | 1999-05-26 | Synphar Lab Inc | Substituted azetidin-2-ones as cysteine protease inhibitors |
| GB9911417D0 (en) | 1999-05-18 | 1999-07-14 | Peptide Therapeutics Ltd | Furanone derivatives as inhibitors of cathepsin s |
| GB9917909D0 (en) | 1999-07-31 | 1999-09-29 | Synphar Lab Inc | Cysteine protease inhibitors |
| JP4203241B2 (ja) | 1999-08-03 | 2008-12-24 | シーメンス アクチエンゲゼルシヤフト | 電気機械的開閉装置のスイッチオフ遅延回路 |
| YU17402A (sh) | 1999-09-13 | 2004-11-25 | Boehringer Ingelheim Pharmaceuticals Inc. | Nova spiroheterociklična jedinjenja upotrebljiva kao reverzibilni inhibitori cisteinskih proteaza |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| CA2384974A1 (en) | 1999-09-16 | 2001-03-22 | Axys Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions as cathepsin s inhibitors |
| GB9925264D0 (en) | 1999-10-26 | 1999-12-29 | Zeneca Ltd | Chemical compounds |
| JP2003513921A (ja) | 1999-11-10 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | プロテア−ゼ阻害剤 |
| WO2001034160A1 (en) | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
| AU783145B2 (en) | 1999-12-24 | 2005-09-29 | F. Hoffmann-La Roche Ag | Nitrile derivatives as cathepsin K inhibitors |
| WO2001049288A1 (en) | 2000-01-06 | 2001-07-12 | Merck Frosst Canada & Co. | Novel compounds and compositions as protease inhibitors |
| GB0003111D0 (en) | 2000-02-10 | 2000-03-29 | Novartis Ag | Organic compounds |
| WO2001068645A2 (en) | 2000-03-15 | 2001-09-20 | Axys Pharmaceuticals, Inc. | N-cyanomethylcarboxamides and their use as protease inhibitors |
| KR20020082896A (ko) | 2000-03-21 | 2002-10-31 | 스미스클라인 비참 코포레이션 | 프로테아제 억제제 |
| WO2001077073A1 (en) | 2000-04-06 | 2001-10-18 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| CO5280093A1 (es) | 2000-04-18 | 2003-05-30 | Smithkline Beecham Corp | Metodos de tratamiento |
| US6462076B2 (en) | 2000-06-14 | 2002-10-08 | Hoffmann-La Roche Inc. | Beta-amino acid nitrile derivatives as cathepsin K inhibitors |
| AU2001268407A1 (en) | 2000-06-14 | 2001-12-24 | Smithkline Beecham Corporation | Protease inhibitors |
| JP2004509083A (ja) | 2000-09-01 | 2004-03-25 | スミスクライン・ビーチャム・コーポレイション | 治療方法 |
| EP1326848A1 (en) | 2000-10-19 | 2003-07-16 | Naeja Pharmaceutical Inc. | Dihydropyrimidine derivatives as cysteine protease inhibitors |
| JP2004523506A (ja) | 2000-12-22 | 2004-08-05 | アクシス・ファーマシューティカルズ・インコーポレイテッド | カテプシン阻害剤としての新規な化合物と組成物 |
| US7425562B2 (en) * | 2001-01-17 | 2008-09-16 | Amura Therapeutics Ltd. | Inhibitors of cruzipain and other cysteine proteases |
| JP2004520365A (ja) | 2001-01-17 | 2004-07-08 | アミュラ テラピューティクス リミテッド | クルジパインおよび他のシステインプロテアーゼの阻害剤 |
| WO2002080920A1 (en) | 2001-04-06 | 2002-10-17 | Axys Pharmaceuticals, Inc. | Arylacetamido-ketobenzoxazole as cysteine protease inhibitors |
| EP1401453A4 (en) | 2001-05-17 | 2005-04-06 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
| FR2826572B1 (fr) | 2001-06-29 | 2005-10-07 | Oreal | Compositions contenant un derive d'hydroxydiphenyl ether inhibant le developpement des odeurs corporelles |
| EP1411933A1 (en) | 2001-08-03 | 2004-04-28 | SmithKline Beecham Corporation | Alpha-ketoamide derivatives as cathepsin k inhibitors |
| AR036375A1 (es) | 2001-08-30 | 2004-09-01 | Novartis Ag | Compuestos pirrolo [2,3-d] pirimidina -2- carbonitrilo, un proceso para su preparacion, una composicion farmaceutica y el uso de dichos compuestos para la preparacion de medicamentos |
| EP1436255A1 (en) | 2001-09-14 | 2004-07-14 | Aventis Pharmaceuticals, Inc. | Novel compounds and compositions as cathepsin inhibitors |
| AU2002340031A1 (en) | 2001-10-02 | 2003-04-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| CA2463770A1 (en) | 2001-10-29 | 2003-05-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| AU2002352663B2 (en) | 2001-11-13 | 2007-06-21 | Axys Pharmaceuticals, Inc. | Cyanoalkylamino derivatives as protease inhibitors |
| YU34604A (sh) | 2001-11-14 | 2006-08-17 | Aventis Pharmaceuticals Inc. | Oligopeptidi kao inhibitori katepsina s i kompozicije koje ih sadrže |
| DE60326473D1 (en) | 2002-07-16 | 2009-04-16 | Amura Therapeutics Ltd | Pyrrolderivate als hemmstoffe von cystein proteasen |
| BRPI0506719A (pt) * | 2004-01-08 | 2007-05-02 | Medivir Ab | composto, composição farmacêutica, e, uso de um composto |
| WO2006064286A1 (en) | 2004-12-13 | 2006-06-22 | Medivir Uk Ltd | Cathepsin s inhibitors |
| GB0614044D0 (en) * | 2006-07-14 | 2006-08-23 | Amura Therapeutics Ltd | Compounds |
| GB0614042D0 (en) * | 2006-07-14 | 2006-08-23 | Amura Therapeutics Ltd | Compounds |
-
2009
- 2009-01-07 EP EP20130189094 patent/EP2719700A1/en not_active Withdrawn
- 2009-01-07 JP JP2010541840A patent/JP5587790B2/ja not_active Expired - Fee Related
- 2009-01-07 WO PCT/GB2009/000039 patent/WO2009087379A2/en not_active Ceased
- 2009-01-07 EP EP09700614.2A patent/EP2240491B1/en not_active Not-in-force
-
2010
- 2010-06-25 US US12/823,558 patent/US8501744B2/en not_active Expired - Fee Related
-
2013
- 2013-05-23 US US13/901,479 patent/US9045492B2/en not_active Expired - Fee Related
-
2015
- 2015-04-10 US US14/683,913 patent/US20150209349A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20130252969A1 (en) | 2013-09-26 |
| WO2009087379A3 (en) | 2009-09-03 |
| EP2240491B1 (en) | 2015-07-15 |
| JP2011509282A (ja) | 2011-03-24 |
| US20110077254A1 (en) | 2011-03-31 |
| EP2719700A1 (en) | 2014-04-16 |
| US9045492B2 (en) | 2015-06-02 |
| EP2240491A2 (en) | 2010-10-20 |
| WO2009087379A2 (en) | 2009-07-16 |
| US8501744B2 (en) | 2013-08-06 |
| US20150209349A1 (en) | 2015-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5587790B2 (ja) | 化合物 | |
| JP5670754B2 (ja) | カテプシンｓ阻害剤としてのフロ［３，２−ｂ］ピロール−３−オン | |
| US8877927B2 (en) | Furo[3,2-B] pyrrol -3-one derivatives and their use as cysteinyl proteinase inhibitors | |
| WO2009144450A1 (en) | Tetrahydrofuro [3, 2-b] pyrrol-3-one derivatives as inhibitors of cysteine proteases | |
| JP2011518120A (ja) | 化合物 | |
| RU2456290C2 (ru) | ТЕТРАГИДРОФУРО(3,2-b)ПИРРОЛ-3-ОНЫ В КАЧЕСТВЕ ИНГИБИТОРОВ КАТЕПСИНА К | |
| EP2078023B1 (en) | Tetrahydrofuro (3, 2-b) pyrrol-3-one derivatives as inhibitors of cysteine proteinases | |
| US8053437B2 (en) | Furo[3. 2-B] pyrrol derivatives | |
| US7846935B2 (en) | Furo[3,2-B]pyrrol-3-one derivatives and their use as cysteinyl proteinase inhibitors | |
| US7846934B2 (en) | Furo[3,2-B] pyrrol-3-one derivatives and their use as cysteinyl proteinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120106 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120106 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130730 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20131029 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20131106 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131224 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140624 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140724 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5587790 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |