CN1255161A - 蛋白酶抑制剂 - Google Patents

蛋白酶抑制剂 Download PDF

Info

Publication number: CN1255161A
Authority: CN; China
Prior art keywords: alkyl; amino; leucine; tetrahydrofuran; het
Prior art date: 1997-05-06
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.): Pending

Application number

CN98804791A

Other languages

English (en)

Chinese (zh)

Inventor

A·D·格里布尔

A·E·芬威克

R·W·马奎斯

D·F·韦贝尔

J·威辛顿

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

SmithKline Beecham Ltd

SmithKline Beecham Corp

Original Assignee

SmithKline Beecham Ltd

SmithKline Beecham Corp

Priority date (The priority date 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 date listed.)

1997-05-06

Filing date

1998-05-06

Publication date

2000-05-31

1998-05-06 Application filed by SmithKline Beecham Ltd, SmithKline Beecham Corp filed Critical SmithKline Beecham Ltd

2000-05-31 Publication of CN1255161A publication Critical patent/CN1255161A/zh

Status Pending legal-status Critical Current

Links

239000000137 peptide hydrolase inhibitor Substances 0.000 title description 4
229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title 1
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 86
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 51
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
201000010099 disease Diseases 0.000 claims abstract description 30
108090000625 Cathepsin K Proteins 0.000 claims abstract description 15
206010065687 Bone loss Diseases 0.000 claims abstract description 7
102000004171 Cathepsin K Human genes 0.000 claims abstract 3
229960003136 leucine Drugs 0.000 claims description 253
150000001875 compounds Chemical class 0.000 claims description 184
238000000034 method Methods 0.000 claims description 116
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 95
-1 isobutyl- Chemical group 0.000 claims description 82
229910052799 carbon Inorganic materials 0.000 claims description 71
229910052739 hydrogen Inorganic materials 0.000 claims description 71
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 63
125000005605 benzo group Chemical group 0.000 claims description 35
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 33
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 32
XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 claims description 28
239000000203 mixture Substances 0.000 claims description 27
150000003839 salts Chemical class 0.000 claims description 27
XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 claims description 21
IFQSXNOEEPCSLW-DKWTVANSSA-N L-cysteine hydrochloride Chemical compound Cl.SC[C@H](N)C(O)=O IFQSXNOEEPCSLW-DKWTVANSSA-N 0.000 claims description 20
CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 16
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
239000000758 substrate Substances 0.000 claims description 12
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 10
210000000845 cartilage Anatomy 0.000 claims description 9
229910052760 oxygen Inorganic materials 0.000 claims description 9
125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 8
229910052717 sulfur Inorganic materials 0.000 claims description 8
201000008482 osteoarthritis Diseases 0.000 claims description 7
238000006243 chemical reaction Methods 0.000 claims description 6
125000000524 functional group Chemical group 0.000 claims description 6
208000024693 gingival disease Diseases 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
230000015556 catabolic process Effects 0.000 claims description 5
238000006731 degradation reaction Methods 0.000 claims description 5
150000001555 benzenes Chemical class 0.000 claims description 4
AWXKVKOGYYLMEL-UHFFFAOYSA-N benzyl n-(4-oxooxolan-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1COCC1=O AWXKVKOGYYLMEL-UHFFFAOYSA-N 0.000 claims description 4
230000000903 blocking effect Effects 0.000 claims description 4
125000005843 halogen group Chemical group 0.000 claims description 4
HQVKXDYSIGDGSY-QWWZWVQMSA-N (3s,4r)-4-aminooxolan-3-ol Chemical compound N[C@@H]1COC[C@H]1O HQVKXDYSIGDGSY-QWWZWVQMSA-N 0.000 claims description 3
RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 2
238000006114 decarboxylation reaction Methods 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000007800 oxidant agent Substances 0.000 claims description 2
230000001590 oxidative effect Effects 0.000 claims description 2
230000001009 osteoporotic effect Effects 0.000 claims 2
230000005764 inhibitory process Effects 0.000 abstract description 11
239000003112 inhibitor Substances 0.000 abstract description 7
102000005927 Cysteine Proteases Human genes 0.000 abstract 1
108010005843 Cysteine Proteases Proteins 0.000 abstract 1
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 abstract 1
YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical group C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 abstract 1
125000001909 leucine group Chemical class [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 abstract 1
239000002585 base Substances 0.000 description 108
238000002360 preparation method Methods 0.000 description 56
239000000243 solution Substances 0.000 description 44
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
238000005160 1H NMR spectroscopy Methods 0.000 description 31
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
230000009467 reduction Effects 0.000 description 21
JLPJFSCQKHRSQR-UHFFFAOYSA-N oxolan-3-one Chemical compound O=C1CCOC1 JLPJFSCQKHRSQR-UHFFFAOYSA-N 0.000 description 20
210000000988 bone and bone Anatomy 0.000 description 19
239000007787 solid Substances 0.000 description 19
238000009834 vaporization Methods 0.000 description 19
230000008016 vaporization Effects 0.000 description 19
238000005406 washing Methods 0.000 description 18
239000007795 chemical reaction product Substances 0.000 description 17
102000004190 Enzymes Human genes 0.000 description 16
108090000790 Enzymes Proteins 0.000 description 16
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
229940024606 amino acid Drugs 0.000 description 14
230000008569 process Effects 0.000 description 14
ZRSGZIMDIHBXIN-UHFFFAOYSA-N 1,3-benzodioxole-5-carbonyl chloride Chemical compound ClC(=O)C1=CC=C2OCOC2=C1 ZRSGZIMDIHBXIN-UHFFFAOYSA-N 0.000 description 13
102100024940 Cathepsin K Human genes 0.000 description 13
235000001014 amino acid Nutrition 0.000 description 13
FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 13
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
210000004027 cell Anatomy 0.000 description 12
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
210000002997 osteoclast Anatomy 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
150000001263 acyl chlorides Chemical class 0.000 description 10
150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
239000006260 foam Substances 0.000 description 10
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
229910000041 hydrogen chloride Inorganic materials 0.000 description 9
239000011259 mixed solution Substances 0.000 description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
239000002904 solvent Substances 0.000 description 9
238000003756 stirring Methods 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
208000001132 Osteoporosis Diseases 0.000 description 8
239000002253 acid Substances 0.000 description 8
238000004440 column chromatography Methods 0.000 description 8
NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
FAHKAHMLFQVMPR-UHFFFAOYSA-N 4-azidooxolan-3-ol Chemical compound OC1COCC1N=[N+]=[N-] FAHKAHMLFQVMPR-UHFFFAOYSA-N 0.000 description 7
108010033040 Histones Proteins 0.000 description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 7
239000012445 acidic reagent Substances 0.000 description 7
150000001413 amino acids Chemical class 0.000 description 7
239000001257 hydrogen Substances 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
DOLJOERLFKHNEY-UHFFFAOYSA-N 3,3-dimethoxyoxolane Chemical compound COC1(OC)CCOC1 DOLJOERLFKHNEY-UHFFFAOYSA-N 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
102000035195 Peptidases Human genes 0.000 description 6
108091005804 Peptidases Proteins 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
239000011324 bead Substances 0.000 description 6
150000002576 ketones Chemical group 0.000 description 6
238000001819 mass spectrum Methods 0.000 description 6
229940002612 prodrug Drugs 0.000 description 6
239000000651 prodrug Substances 0.000 description 6
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
239000000376 reactant Substances 0.000 description 6
239000011541 reaction mixture Substances 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
235000017557 sodium bicarbonate Nutrition 0.000 description 6
PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
239000007788 liquid Substances 0.000 description 5
201000001245 periodontitis Diseases 0.000 description 5
238000012545 processing Methods 0.000 description 5
JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
208000010191 Osteitis Deformans Diseases 0.000 description 4
208000027868 Paget disease Diseases 0.000 description 4
239000004365 Protease Substances 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
125000000217 alkyl group Chemical group 0.000 description 4
230000008878 coupling Effects 0.000 description 4
238000010168 coupling process Methods 0.000 description 4
238000005859 coupling reaction Methods 0.000 description 4
239000013078 crystal Substances 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
125000000623 heterocyclic group Chemical group 0.000 description 4
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
239000000543 intermediate Substances 0.000 description 4
208000027202 mammary Paget disease Diseases 0.000 description 4
239000011159 matrix material Substances 0.000 description 4
125000001624 naphthyl group Chemical group 0.000 description 4
108090000765 processed proteins & peptides Proteins 0.000 description 4
235000019419 proteases Nutrition 0.000 description 4
235000018102 proteins Nutrition 0.000 description 4
102000004169 proteins and genes Human genes 0.000 description 4
108090000623 proteins and genes Proteins 0.000 description 4
238000010898 silica gel chromatography Methods 0.000 description 4
JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
210000001519 tissue Anatomy 0.000 description 4
NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 3
JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
241000222716 Crithidia Species 0.000 description 3
239000004395 L-leucine Substances 0.000 description 3
QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 3
USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 3
241000233872 Pneumocystis carinii Species 0.000 description 3
239000012980 RPMI-1640 medium Substances 0.000 description 3
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
239000007864 aqueous solution Substances 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
238000013016 damping Methods 0.000 description 3
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
229940079593 drug Drugs 0.000 description 3
238000001035 drying Methods 0.000 description 3
238000010828 elution Methods 0.000 description 3
238000003810 ethyl acetate extraction Methods 0.000 description 3
238000000605 extraction Methods 0.000 description 3
239000012530 fluid Substances 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
150000002240 furans Chemical class 0.000 description 3
230000000148 hypercalcaemia Effects 0.000 description 3
208000030915 hypercalcemia disease Diseases 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
230000003211 malignant effect Effects 0.000 description 3
230000001394 metastastic effect Effects 0.000 description 3
206010061289 metastatic neoplasm Diseases 0.000 description 3
229930182817 methionine Natural products 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
230000007170 pathology Effects 0.000 description 3
239000002953 phosphate buffered saline Substances 0.000 description 3
239000000047 product Substances 0.000 description 3
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000011347 resin Substances 0.000 description 3
229920005989 resin Polymers 0.000 description 3
238000000926 separation method Methods 0.000 description 3
239000000725 suspension Substances 0.000 description 3
229960004799 tryptophan Drugs 0.000 description 3
210000004881 tumor cell Anatomy 0.000 description 3
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
XFDDJSOAVIFVIH-VKKIDBQXSA-N (3s,4r)-4-aminooxolan-3-ol;hydrochloride Chemical compound Cl.N[C@@H]1COC[C@H]1O XFDDJSOAVIFVIH-VKKIDBQXSA-N 0.000 description 2
FAHKAHMLFQVMPR-QWWZWVQMSA-N (3s,4r)-4-azidooxolan-3-ol Chemical compound O[C@@H]1COC[C@H]1N=[N+]=[N-] FAHKAHMLFQVMPR-QWWZWVQMSA-N 0.000 description 2
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 2
DNGLRCHMGDDHNC-UHFFFAOYSA-N 1-benzothiophene-2-carbonyl chloride Chemical compound C1=CC=C2SC(C(=O)Cl)=CC2=C1 DNGLRCHMGDDHNC-UHFFFAOYSA-N 0.000 description 2
IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
239000004475 Arginine Substances 0.000 description 2
229940122156 Cathepsin K inhibitor Drugs 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
239000006145 Eagle's minimal essential medium Substances 0.000 description 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-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
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
208000002720 Malnutrition Diseases 0.000 description 2
241000124008 Mammalia Species 0.000 description 2
208000030136 Marchiafava-Bignami Disease Diseases 0.000 description 2
208000029725 Metabolic bone disease Diseases 0.000 description 2
206010027476 Metastases Diseases 0.000 description 2
XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
206010028980 Neoplasm Diseases 0.000 description 2
QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
206010039361 Sacroiliitis Diseases 0.000 description 2
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
102000008847 Serpin Human genes 0.000 description 2
108050000761 Serpin Proteins 0.000 description 2
101710172711 Structural protein Proteins 0.000 description 2
239000006035 Tryptophane Substances 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
235000003704 aspartic acid Nutrition 0.000 description 2
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
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 2
239000007844 bleaching agent Substances 0.000 description 2
KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
238000005119 centrifugation Methods 0.000 description 2
238000011097 chromatography purification Methods 0.000 description 2
230000006837 decompression Effects 0.000 description 2
210000004268 dentin Anatomy 0.000 description 2
238000010790 dilution Methods 0.000 description 2
239000012895 dilution Substances 0.000 description 2
230000000694 effects Effects 0.000 description 2
ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
229910052736 halogen Inorganic materials 0.000 description 2
150000002367 halogens Chemical class 0.000 description 2
125000005842 heteroatom Chemical group 0.000 description 2
238000005984 hydrogenation reaction Methods 0.000 description 2
229910052588 hydroxylapatite Inorganic materials 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
229960000310 isoleucine Drugs 0.000 description 2
AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
235000015110 jellies Nutrition 0.000 description 2
239000008274 jelly Substances 0.000 description 2
201000004792 malaria Diseases 0.000 description 2
230000001071 malnutrition Effects 0.000 description 2
235000000824 malnutrition Nutrition 0.000 description 2
OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
238000002156 mixing Methods 0.000 description 2
210000001616 monocyte Anatomy 0.000 description 2
201000006938 muscular dystrophy Diseases 0.000 description 2
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
208000015380 nutritional deficiency disease Diseases 0.000 description 2
239000003921 oil Substances 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
238000007254 oxidation reaction Methods 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
XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
229920001184 polypeptide Polymers 0.000 description 2
102000004196 processed proteins & peptides Human genes 0.000 description 2
SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 2
230000002797 proteolythic effect Effects 0.000 description 2
238000000746 purification Methods 0.000 description 2
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
230000036632 reaction speed Effects 0.000 description 2
239000000523 sample Substances 0.000 description 2
230000001843 schistosomicidal effect Effects 0.000 description 2
108010048734 sclerotin Proteins 0.000 description 2
229960001153 serine Drugs 0.000 description 2
239000003001 serine protease inhibitor Substances 0.000 description 2
229910000029 sodium carbonate Inorganic materials 0.000 description 2
PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 2
239000000126 substance Substances 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
238000001308 synthesis method Methods 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
231100000331 toxic Toxicity 0.000 description 2
230000002588 toxic effect Effects 0.000 description 2
JYGRAOYMDDFOSM-FQJIPJFPSA-N (4s)-4-[[(2s)-4-carboxy-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]propanoyl]amino]butanoyl]amino]-5-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentano Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN JYGRAOYMDDFOSM-FQJIPJFPSA-N 0.000 description 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
VJYJBBMMLIDJEF-UHFFFAOYSA-N 1-benzothiophen-2-amine Chemical compound C1=CC=C2SC(N)=CC2=C1 VJYJBBMMLIDJEF-UHFFFAOYSA-N 0.000 description 1
QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
AIUTZIYTEUMXGG-UHFFFAOYSA-N 3,6-dioxabicyclo[3.1.0]hexane Chemical compound C1OCC2OC12 AIUTZIYTEUMXGG-UHFFFAOYSA-N 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
VKASZGOUBGIDCS-UHFFFAOYSA-N 4,4-dimethoxyoxolan-3-amine Chemical compound COC1(OC)COCC1N VKASZGOUBGIDCS-UHFFFAOYSA-N 0.000 description 1
CMOPZQRVDYLJMW-UHFFFAOYSA-N 4-amino-2H-benzotriazol-5-ol Chemical compound Nc1c(O)ccc2n[nH]nc12 CMOPZQRVDYLJMW-UHFFFAOYSA-N 0.000 description 1
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
BLQJZTXYHZLWJC-UHFFFAOYSA-N 4-methylpyridine-3-carbonyl chloride Chemical compound CC1=CC=NC=C1C(Cl)=O BLQJZTXYHZLWJC-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
108010088751 Albumins Proteins 0.000 description 1
102000009027 Albumins Human genes 0.000 description 1
102000003916 Arrestin Human genes 0.000 description 1
108090000328 Arrestin Proteins 0.000 description 1
CKLJMWTZIZZHCS-UHFFFAOYSA-N Aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
241000894006 Bacteria Species 0.000 description 1
208000010392 Bone Fractures Diseases 0.000 description 1
208000020084 Bone disease Diseases 0.000 description 1
229940078581 Bone resorption inhibitor Drugs 0.000 description 1
JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
102000055006 Calcitonin Human genes 0.000 description 1
108060001064 Calcitonin Proteins 0.000 description 1
241000283707 Capra Species 0.000 description 1
108090000712 Cathepsin B Proteins 0.000 description 1
102000004225 Cathepsin B Human genes 0.000 description 1
108090000619 Cathepsin H Proteins 0.000 description 1
108090000624 Cathepsin L Proteins 0.000 description 1
101710177066 Cathepsin O Proteins 0.000 description 1
108090000613 Cathepsin S Proteins 0.000 description 1
102000005600 Cathepsins Human genes 0.000 description 1
108010084457 Cathepsins Proteins 0.000 description 1
102000012422 Collagen Type I Human genes 0.000 description 1
108010022452 Collagen Type I Proteins 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
102000015833 Cystatin Human genes 0.000 description 1
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
241001379910 Ephemera danica Species 0.000 description 1
239000004593 Epoxy Substances 0.000 description 1
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
102000016359 Fibronectins Human genes 0.000 description 1
108010067306 Fibronectins Proteins 0.000 description 1
206010017076 Fracture Diseases 0.000 description 1
208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 1
108091020100 Gingipain Cysteine Endopeptidases Proteins 0.000 description 1
SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
239000004471 Glycine Substances 0.000 description 1
101000761509 Homo sapiens Cathepsin K Proteins 0.000 description 1
208000037147 Hypercalcaemia Diseases 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
206010061218 Inflammation Diseases 0.000 description 1
102000016921 Integrin-Binding Sialoprotein Human genes 0.000 description 1
108010028750 Integrin-Binding Sialoprotein Proteins 0.000 description 1
VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
238000005481 NMR spectroscopy Methods 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
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 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
102000018120 Recombinases Human genes 0.000 description 1
108010091086 Recombinases Proteins 0.000 description 1
BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
102000002938 Thrombospondin Human genes 0.000 description 1
108060008245 Thrombospondin Proteins 0.000 description 1
208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
208000027418 Wounds and injury Diseases 0.000 description 1
239000008351 acetate buffer Substances 0.000 description 1
229960000583 acetic acid Drugs 0.000 description 1
230000009471 action Effects 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
125000003158 alcohol group Chemical group 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
239000003513 alkali Substances 0.000 description 1
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
238000013459 approach Methods 0.000 description 1
235000009697 arginine Nutrition 0.000 description 1
230000002917 arthritic effect Effects 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
ZZGDDBWFXDMARY-SVBPBHIXSA-N benzyl n-[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC1=CC=2OC(=O)C=C(C=2C=C1)C)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 ZZGDDBWFXDMARY-SVBPBHIXSA-N 0.000 description 1
238000004166 bioassay Methods 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
239000008280 blood Substances 0.000 description 1
230000036765 blood level Effects 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
238000000339 bright-field microscopy Methods 0.000 description 1
IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
238000004364 calculation method Methods 0.000 description 1
244000309466 calf Species 0.000 description 1
FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
108010015574 cathepsin N Proteins 0.000 description 1
230000008859 change Effects 0.000 description 1
DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 1
210000003541 chondroclast Anatomy 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
239000012230 colorless oil Substances 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
239000002299 complementary DNA Substances 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
239000013068 control sample Substances 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
108050004038 cystatin Proteins 0.000 description 1
230000002354 daily effect Effects 0.000 description 1
238000007405 data analysis Methods 0.000 description 1
108010053500 delicious peptide Proteins 0.000 description 1
238000013461 design Methods 0.000 description 1
XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
238000007876 drug discovery Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
150000002118 epoxides Chemical class 0.000 description 1
238000010931 ester hydrolysis Methods 0.000 description 1
239000000328 estrogen antagonist Substances 0.000 description 1
YVKSGVDJQXLXDV-BYPYZUCNSA-N ethyl (2r)-2-amino-3-sulfanylpropanoate Chemical compound CCOC(=O)[C@@H](N)CS YVKSGVDJQXLXDV-BYPYZUCNSA-N 0.000 description 1
MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
230000003203 everyday effect Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
238000001914 filtration Methods 0.000 description 1
238000009472 formulation Methods 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
239000002223 garnet Substances 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
229960002989 glutamic acid Drugs 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
229960002743 glutamine Drugs 0.000 description 1
229960002449 glycine Drugs 0.000 description 1
230000012447 hatching Effects 0.000 description 1
KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
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 1
230000003284 homeostatic effect Effects 0.000 description 1
238000002657 hormone replacement therapy Methods 0.000 description 1
102000049698 human CTSK Human genes 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
230000006872 improvement Effects 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
208000015181 infectious disease Diseases 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000011081 inoculation Methods 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
239000011630 iodine Substances 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
125000005956 isoquinolyl group Chemical group 0.000 description 1
125000001786 isothiazolyl group Chemical group 0.000 description 1
CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
238000012886 linear function Methods 0.000 description 1
125000005647 linker group Chemical group 0.000 description 1
230000002503 metabolic effect Effects 0.000 description 1
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical class COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical class COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
244000000010 microbial pathogen Species 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
230000002969 morbid Effects 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
235000011837 pasties Nutrition 0.000 description 1
230000008506 pathogenesis Effects 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
208000028169 periodontal disease Diseases 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
230000035790 physiological processes and functions Effects 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000005936 piperidyl group Chemical group 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000013641 positive control Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
239000012268 protein inhibitor Substances 0.000 description 1
229940121649 protein inhibitor Drugs 0.000 description 1
230000017854 proteolysis Effects 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
WFVMVMAUXYOQSW-UHFFFAOYSA-N quinoline-2-carbonyl chloride Chemical compound C1=CC=CC2=NC(C(=O)Cl)=CC=C21 WFVMVMAUXYOQSW-UHFFFAOYSA-N 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
239000002994 raw material Substances 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
230000000452 restraining effect Effects 0.000 description 1
230000000630 rising effect Effects 0.000 description 1
239000011435 rock Substances 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000012216 screening Methods 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
239000012453 solvate Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
238000003860 storage Methods 0.000 description 1
150000003457 sulfones Chemical class 0.000 description 1
210000001258 synovial membrane Anatomy 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
238000003419 tautomerization reaction Methods 0.000 description 1
238000012360 testing method Methods 0.000 description 1
150000003527 tetrahydropyrans Chemical class 0.000 description 1
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000002769 thiazolinyl group Chemical group 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
229960004441 tyrosine Drugs 0.000 description 1
239000003981 vehicle Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/99—Enzyme inactivation by chemical treatment
- 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
- 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
- A61P21/06—Anabolic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Physical Education & Sports Medicine (AREA)
Medicinal Chemistry (AREA)
General Chemical & Material Sciences (AREA)
General Health & Medical Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Orthopedic Medicine & Surgery (AREA)
Rheumatology (AREA)
Wood Science & Technology (AREA)
Zoology (AREA)
Genetics & Genomics (AREA)
Immunology (AREA)
Molecular Biology (AREA)
Microbiology (AREA)
Biochemistry (AREA)
General Engineering & Computer Science (AREA)
Biotechnology (AREA)
Biomedical Technology (AREA)
Endocrinology (AREA)
Neurology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Peptides Or Proteins (AREA)

CN98804791A 1997-05-06 1998-05-06 蛋白酶抑制剂 Pending CN1255161A (zh)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US4575897P	1997-05-06	1997-05-06
US60/045,758		1997-05-06

Publications (1)

Publication Number	Publication Date
CN1255161A true CN1255161A (zh)	2000-05-31

Family

ID=21939723

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CN98804791A Pending CN1255161A (zh)	1997-05-06	1998-05-06	蛋白酶抑制剂

Country Status (19)

Country	Link
EP (1)	EP1003846A4 (fr)
JP (1)	JP2001525804A (fr)
KR (1)	KR20010012256A (fr)
CN (1)	CN1255161A (fr)
AR (1)	AR013079A1 (fr)
AU (1)	AU7562598A (fr)
BR (1)	BR9809306A (fr)
CA (1)	CA2288868A1 (fr)
CO (1)	CO4950618A1 (fr)
HU (1)	HUP0002247A3 (fr)
IL (1)	IL132088A0 (fr)
NO (1)	NO995434L (fr)
NZ (1)	NZ337889A (fr)
PE (1)	PE71599A1 (fr)
PL (1)	PL336856A1 (fr)
TR (1)	TR199902766T2 (fr)
UY (1)	UY25143A1 (fr)
WO (1)	WO1998050533A1 (fr)
ZA (1)	ZA983762B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN100354276C (zh) *	2002-07-16	2007-12-12	阿姆拉医疗有限公司	生物活性化合物
CN102224156A (zh) *	2008-09-24	2011-10-19	美迪维尔公司	蛋白酶抑制剂

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CO5150165A1 (es) *	1998-11-13	2002-04-29	Smithkline Beecham Plc	Inhibidores de proteasa: tipo catepsina k
DZ3083A1 (fr) *	1999-02-19	2004-06-02	Smithkline Beecham Corp	Composés nouveaux inhibiteurs de protéases, procédé pour leur préparation et compositions pharmaceutiques les conentant.
GB9911417D0 (en) *	1999-05-18	1999-07-14	Peptide Therapeutics Ltd	Furanone derivatives as inhibitors of cathepsin s
EP1232155A4 (fr) *	1999-11-10	2002-11-20	Smithkline Beecham Corp	Inhibiteurs de protease
US20040024000A1 (en) *	2000-10-19	2004-02-05	Rajeshwar Singh	Dihydropyrimidine derivatives as cysteine protease inhibitors
EP1345931A2 (fr) *	2000-11-17	2003-09-24	Medivir UK Ltd	Inhibiteurs de cysteine protease
DE60118793T2 (de) *	2000-11-17	2007-04-26	Medivir Ab	Cystein protease inhibitoren
PT1362052E (pt)	2001-01-17	2007-04-30	Amura Therapeutics Ltd	Inibidores de cruzipaína e de outras proteases de cisteína
US7132449B2 (en)	2001-01-17	2006-11-07	Amura Therapeutics Limited	Inhibitors of cruzipain and other cysteine proteases
CA2435117A1 (fr) *	2001-01-17	2002-07-25	Amura Therapeutics Limited	2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres 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
US6841571B2 (en) *	2001-10-29	2005-01-11	Boehringer Ingelheim Pharmaceuticals, Inc.	Compounds useful as reversible inhibitors of cysteine proteases
KR100962972B1 (ko)	2002-07-26	2010-06-09	주식회사유한양행	1-페닐피페리딘-3-온 유도체 및 그의 제조방법
WO2005041684A2 (fr)	2003-08-06	2005-05-12	Senomyx Inc.	Saveurs, modificateurs de saveur, agents gustatifs, rehausseurs de gout, agents gustatifs et/ou rehausseurs umami ou sucres, et utilisation correspondante
AU2016206281B2 (en) *	2003-08-06	2017-11-30	Senomyx, Inc.	Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
BRPI0506719A (pt) *	2004-01-08	2007-05-02	Medivir Ab	composto, composição farmacêutica, e, uso de um composto
EP1931657B1 (fr) *	2005-08-17	2013-12-25	Merck Sharp & Dohme Corp.	Nouveaux ligands de kinases a base de quinoline a affinite elevee
GB0614042D0 (en)	2006-07-14	2006-08-23	Amura Therapeutics Ltd	Compounds
AU2008266228A1 (en) *	2007-06-13	2008-12-24	Bristol-Myers Squibb Company	Dipeptide analogs as coagulation factor inhibitors
US7893067B2 (en)	2007-06-27	2011-02-22	Medivir Ab	Cysteine protease inhibitors
WO2009087379A2 (fr)	2008-01-09	2009-07-16	Amura Therapeutics Limited	Composés

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP3190431B2 (ja) *	1991-07-01	2001-07-23	三菱化学株式会社	ケトン誘導体
JPH05140063A (ja) *	1991-11-19	1993-06-08	Suntory Ltd	ジペプチド誘導体及びそれを有効成分とする骨疾患の予防及び治療剤
CA2111930A1 (fr) *	1992-12-25	1994-06-26	Ryoichi Ando	Derives d'aminocetones
JP2848232B2 (ja) *	1993-02-19	1999-01-20	武田薬品工業株式会社	アルデヒド誘導体
JP3599287B2 (ja) *	1993-04-28	2004-12-08	三菱化学株式会社	スルホンアミド誘導体
US5403952A (en) *	1993-10-08	1995-04-04	Merck & Co., Inc.	Substituted cyclic derivatives as novel antidegenerative agents
PL328877A1 (en) *	1995-10-30	1999-03-01	Smithkline Beecham Corp	Method of inhibiting cathepsin k
TW448172B (en) *	1996-03-08	2001-08-01	Pharmacia & Upjohn Co Llc	Novel hydroxamic acid derivatives useful for the treatment of diseases related to connective tissue degradation
WO1998004539A1 (fr) *	1996-07-29	1998-02-05	Mitsubishi Chemical Corporation	Derives heterocycliques oxygenes

1998
- 1998-05-04 AR ARP980102069A patent/AR013079A1/es unknown
- 1998-05-05 PE PE1998000336A patent/PE71599A1/es not_active Application Discontinuation
- 1998-05-05 ZA ZA983762A patent/ZA983762B/xx unknown
- 1998-05-06 NZ NZ337889A patent/NZ337889A/en unknown
- 1998-05-06 HU HU0002247A patent/HUP0002247A3/hu unknown
- 1998-05-06 BR BR9809306-1A patent/BR9809306A/pt not_active Application Discontinuation
- 1998-05-06 EP EP98923299A patent/EP1003846A4/fr not_active Withdrawn
- 1998-05-06 CN CN98804791A patent/CN1255161A/zh active Pending
- 1998-05-06 IL IL13208898A patent/IL132088A0/xx unknown
- 1998-05-06 CO CO98024945A patent/CO4950618A1/es unknown
- 1998-05-06 PL PL98336856A patent/PL336856A1/xx unknown
- 1998-05-06 KR KR1019997010207A patent/KR20010012256A/ko not_active Application Discontinuation
- 1998-05-06 WO PCT/US1998/003200 patent/WO1998050533A1/fr not_active Application Discontinuation
- 1998-05-06 CA CA002288868A patent/CA2288868A1/fr not_active Abandoned
- 1998-05-06 JP JP54804998A patent/JP2001525804A/ja active Pending
- 1998-05-06 TR TR1999/02766T patent/TR199902766T2/xx unknown
- 1998-05-06 AU AU75625/98A patent/AU7562598A/en not_active Abandoned
- 1998-08-17 UY UY25143A patent/UY25143A1/es unknown
1999
- 1999-11-05 NO NO995434A patent/NO995434L/no not_active Application Discontinuation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN100354276C (zh) *	2002-07-16	2007-12-12	阿姆拉医疗有限公司	生物活性化合物
CN102224156A (zh) *	2008-09-24	2011-10-19	美迪维尔公司	蛋白酶抑制剂
CN102224156B (zh) *	2008-09-24	2014-06-25	美迪维尔公司	蛋白酶抑制剂

Also Published As

Publication number	Publication date
EP1003846A4 (fr)	2002-11-13
IL132088A0 (en)	2001-03-19
AU7562598A (en)	1998-11-27
AR013079A1 (es)	2000-12-13
HUP0002247A3 (en)	2003-01-28
PL336856A1 (en)	2000-07-17
WO1998050533A1 (fr)	1998-11-12
ZA983762B (en)	1998-11-06
UY25143A1 (es)	1998-11-27
KR20010012256A (ko)	2001-02-15
NZ337889A (en)	2001-09-28
HUP0002247A2 (hu)	2001-05-28
NO995434D0 (no)	1999-11-05
CA2288868A1 (fr)	1998-11-12
NO995434L (no)	1999-11-05
EP1003846A1 (fr)	2000-05-31
CO4950618A1 (es)	2000-09-01
PE71599A1 (es)	1999-09-15
TR199902766T2 (xx)	2000-02-21
JP2001525804A (ja)	2001-12-11
BR9809306A (pt)	2000-07-04

Legal Events

Date	Code	Title
2000-05-31	C06	Publication
2000-05-31	PB01	Publication
2001-02-28	C01	Deemed withdrawal of patent application (patent law 1993)
2001-02-28	WD01	Invention patent application deemed withdrawn after publication

Publication	Publication Date	Title
CN1255161A (zh)	2000-05-31	蛋白酶抑制剂
CN1303066C (zh)	2007-03-07	2－氧代－1－吡咯烷衍生物、其制备方法和用途
CN1317278C (zh)	2007-05-23	新杂环化合物及它们作为药物的用途
CN1255162A (zh)	2000-05-31	蛋白酶抑制剂
CN1331688A (zh)	2002-01-16	氨基吡啶衍生物
CN1246311C (zh)	2006-03-22	抑制环腺苷酸特异性磷酸二酯酶的吡咯烷
CN1694879A (zh)	2005-11-09	具有激酶抑制活性的异喹啉衍生物和包含异喹啉衍生物的药剂
CN1538968A (zh)	2004-10-20	新型化合物
WO2015113452A1 (fr)	2015-08-06	Composés
CN1377347A (zh)	2002-10-30	药学活性磺酰胺衍生物
CN1555367A (zh)	2004-12-15	3-取代的-4-嘧啶酮衍生物
CN1294126C (zh)	2007-01-10	N－苯基芳基磺酰胺化合物、包括该化合物作为活性成分的药物组合物、该化合物的合成中间体及其制备方法
CN1038586C (zh)	1998-06-03	吡嗪衍生物的制备方法
CN1571786A (zh)	2005-01-26	烷基醚衍生物或其盐
CN1119856A (zh)	1996-04-03	Hiv逆转录酶抑制剂
CN1561338A (zh)	2005-01-05	作为5－羟基色胺－6配体的苯并二氢吡喃衍生物
CN1079396C (zh)	2002-02-20	用作选择性凝血酶抑制剂的芳族脒衍生物
CN1606443A (zh)	2005-04-13	作为催产素拮抗剂的取代的二酮哌嗪类
CN1437600A (zh)	2003-08-20	作为抗病毒剂的吡咯并喹诺酮
CN1278820A (zh)	2001-01-03	作为嗜中性粒细胞弹性蛋白酶抑制剂的吡咯并吡咯酮衍生物
CN1221539C (zh)	2005-10-05	紫杉烷衍生物
CN1202096C (zh)	2005-05-18	2－氨基噻唑啉衍生物及其作为no－合酶抑制剂的用途
CN1726210A (zh)	2006-01-25	对gsk3具有选择性抑制作用的新型化合物
CN1512993A (zh)	2004-07-14	咪唑三嗪酮类衍生物及其对抗炎症进程和/或免疫疾病的用途
CN1028531C (zh)	1995-05-24	1-氧杂-2-氧代-8-氮杂螺[4，5]癸烷衍生物及其盐的制备方法