CA2369970A1 - Hepatitis c inhibitor tri-peptides - Google Patents
Hepatitis c inhibitor tri-peptides Download PDFInfo
- Publication number
- CA2369970A1 CA2369970A1 CA002369970A CA2369970A CA2369970A1 CA 2369970 A1 CA2369970 A1 CA 2369970A1 CA 002369970 A CA002369970 A CA 002369970A CA 2369970 A CA2369970 A CA 2369970A CA 2369970 A1 CA2369970 A1 CA 2369970A1
- Authority
- CA
- Canada
- Prior art keywords
- hepatitis
- formula
- compound
- hcv
- alkyl
- 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.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title claims description 21
- 208000006454 hepatitis Diseases 0.000 title description 3
- 231100000283 hepatitis Toxicity 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 150000002148 esters Chemical class 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 241000711549 Hepacivirus C Species 0.000 claims description 48
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- 208000005176 Hepatitis C Diseases 0.000 claims description 20
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- -1 polymerase Proteins 0.000 claims description 17
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 230000009385 viral infection Effects 0.000 claims description 9
- 208000036142 Viral infection Diseases 0.000 claims description 8
- 229940079322 interferon Drugs 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 6
- 108010050904 Interferons Proteins 0.000 claims description 6
- 241000700605 Viruses Species 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000003612 virological effect Effects 0.000 claims description 6
- 230000010076 replication Effects 0.000 claims description 4
- 241000490229 Eucephalus Species 0.000 claims description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
- 229960000329 ribavirin Drugs 0.000 claims description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 3
- 108060004795 Methyltransferase Proteins 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims description 2
- 102000005741 Metalloproteases Human genes 0.000 claims 1
- 108010006035 Metalloproteases Proteins 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 23
- 125000003118 aryl group Chemical group 0.000 abstract description 13
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 7
- 125000005843 halogen group Chemical group 0.000 abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 5
- 229910052799 carbon Inorganic materials 0.000 abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 abstract description 4
- 150000001408 amides Chemical class 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract 3
- 125000003368 amide group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000002252 acyl group Chemical group 0.000 abstract 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 abstract 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000004966 cyanoalkyl group Chemical group 0.000 abstract 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 abstract 1
- 125000001188 haloalkyl group Chemical group 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 125000004001 thioalkyl group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 108090000765 processed proteins & peptides Proteins 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 101710144111 Non-structural protein 3 Proteins 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 150000003254 radicals Chemical class 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 108091005804 Peptidases Proteins 0.000 description 12
- 239000004365 Protease Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- 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
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 101800001020 Non-structural protein 4A Proteins 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000001488 sodium phosphate Substances 0.000 description 5
- 229910000162 sodium phosphate Inorganic materials 0.000 description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 108010076039 Polyproteins Proteins 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 3
- 208000006154 Chronic hepatitis C Diseases 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 108010067372 Pancreatic elastase Proteins 0.000 description 3
- 102000016387 Pancreatic elastase Human genes 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 208000010710 hepatitis C virus infection Diseases 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 235000012976 tarts Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 244000309456 Decussocarpus nagi Species 0.000 description 2
- 235000008375 Decussocarpus nagi Nutrition 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 2
- 101800001019 Non-structural protein 4B Proteins 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 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
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BHMLFPOTZYRDKA-IRXDYDNUSA-N (2s)-2-[(s)-(2-iodophenoxy)-phenylmethyl]morpholine Chemical compound IC1=CC=CC=C1O[C@@H](C=1C=CC=CC=1)[C@H]1OCCNC1 BHMLFPOTZYRDKA-IRXDYDNUSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- RRWZZMHRVSMLCT-UHFFFAOYSA-N 2-(butylazaniumyl)acetate Chemical compound CCCCNCC(O)=O RRWZZMHRVSMLCT-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- PBVAJRFEEOIAGW-UHFFFAOYSA-N 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP(CCC(O)=O)CCC(O)=O PBVAJRFEEOIAGW-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 description 1
- XJGFWWJLMVZSIG-UHFFFAOYSA-N 9-aminoacridine Chemical compound C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 XJGFWWJLMVZSIG-UHFFFAOYSA-N 0.000 description 1
- 241000023308 Acca Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 102220495975 BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like_N84A_mutation Human genes 0.000 description 1
- 101150106671 COMT gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 241000320892 Clerodendrum phlomidis Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229940122604 HCV protease inhibitor Drugs 0.000 description 1
- 206010019773 Hepatitis G Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001455213 Leopardus pardalis Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 101100450563 Mus musculus Serpind1 gene Proteins 0.000 description 1
- 102100033174 Neutrophil elastase Human genes 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101710180319 Protease 1 Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102220593424 Protein PMS2CL_N34A_mutation Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241001653634 Russula vesca Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 101710137710 Thioesterase 1/protease 1/lysophospholipase L1 Proteins 0.000 description 1
- 108030003004 Triphosphatases Proteins 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 108700022715 Viral Proteases Proteins 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
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 101150067977 ap gene Proteins 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000012888 bovine serum Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 108700012707 hepatitis C virus NS3 Proteins 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- WZVXLJYENHHFPD-UHFFFAOYSA-N methylaminomethanol;hydrochloride Chemical compound Cl.CNCO WZVXLJYENHHFPD-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 230000000149 penetrating 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
- 229960005190 phenylalanine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- MEFOUWRMVYJCQC-UHFFFAOYSA-N rimsulfuron Chemical compound CCS(=O)(=O)C1=CC=CN=C1S(=O)(=O)NC(=O)NC1=NC(OC)=CC(OC)=N1 MEFOUWRMVYJCQC-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000008957 viral persistence Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (32)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002369970A CA2369970A1 (en) | 2002-02-01 | 2002-02-01 | Hepatitis c inhibitor tri-peptides |
| US10/320,979 US20030191067A1 (en) | 2002-02-01 | 2002-12-17 | Hepatitis C inhibitor tri-peptides |
| CA2474031A CA2474031C (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| NZ534730A NZ534730A (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis C inhibitors |
| AT03700745T ATE369364T1 (de) | 2002-02-01 | 2003-01-24 | Heterocyclische tripeptide als hepatitis c- inhibitoren |
| CNB038061619A CN1304416C (zh) | 2002-02-01 | 2003-01-24 | 作为c型肝炎抑制剂的杂环三肽 |
| JP2003564039A JP4073872B2 (ja) | 2002-02-01 | 2003-01-24 | Ｃ型肝炎阻害剤としての複素環式トリペプチド |
| UA20040807171A UA77757C2 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c virus inhibitors |
| MXPA04007446A MXPA04007446A (es) | 2002-02-01 | 2003-01-24 | Tripeptidos heterociclicos como inhibidores de hepatitis c. |
| PL03371283A PL371283A1 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| HK05110947.8A HK1078870B (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| PCT/CA2003/000091 WO2003064416A1 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| BR0307517-6A BR0307517A (pt) | 2002-02-01 | 2003-01-24 | Tripeptìdeos heterocìclicos como inibidores de hepatite c |
| KR10-2004-7011888A KR20040081167A (ko) | 2002-02-01 | 2003-01-24 | Ｃ형 간염 억제제로서의 헤테로사이클릭 트리펩티드 |
| ES03700745T ES2290425T3 (es) | 2002-02-01 | 2003-01-24 | Tripeptidos heterociclicos en calidad de inhibidores de la hepatitis c. |
| DE60315420T DE60315420T2 (de) | 2002-02-01 | 2003-01-24 | Heterocyclische tripeptide als hepatitis c-inhibitoren |
| EA200400986A EA007739B1 (ru) | 2002-02-01 | 2003-01-24 | Гетероциклические трипептиды в качестве ингибиторов вируса гепатита с |
| EP03700745A EP1474423B1 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| YU67104A RS67104A (sr) | 2002-02-01 | 2003-01-24 | Heterociklični tripeptidi kao inhibitori hepatitisa c |
| AU2003202348A AU2003202348B2 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| HR20040696A HRP20040696A2 (en) | 2002-02-01 | 2003-01-24 | Heterocyclic tripeptides as hepatitis c inhibitors |
| US10/353,563 US7091184B2 (en) | 2002-02-01 | 2003-01-29 | Hepatitis C inhibitor tri-peptides |
| TW092102240A TWI274056B (en) | 2002-02-01 | 2003-01-30 | Hepatitis C inhibitor compound |
| PE2003000105A PE20030854A1 (es) | 2002-02-01 | 2003-01-30 | Compuesto inhibidor de la hepatitis c |
| MYPI20030338A MY133719A (en) | 2002-02-01 | 2003-01-30 | Hepatitis c inhibitor tri-peptides |
| ARP030100291A AR038382A1 (es) | 2002-02-01 | 2003-01-31 | Compuesto inhibidor de la hepatitis c |
| UY27638A UY27638A1 (es) | 2002-02-01 | 2003-01-31 | Compuesto inhibidor de la hepatitis c |
| SA03240006A SA03240006B1 (ar) | 2002-02-01 | 2003-03-05 | مركب مثبط لالتهاب الكبد c |
| ZA200406014A ZA200406014B (en) | 2002-02-01 | 2004-07-28 | Heterocyclic tripeptides as Hepatitis C inhibitors |
| EC2004005224A ECSP045224A (es) | 2002-02-01 | 2004-08-09 | Tripéptidos inhibidores de la hepatitis c |
| NO20043642A NO326421B1 (no) | 2002-02-01 | 2004-08-31 | Heterocykiske tripeptider, farmasoytisk preparat omfattende slike samt anvendelse av slike for fremstilling av medikamenter for behandling eller forebygging av sykdom |
| CO04085343A CO5611112A2 (es) | 2002-02-01 | 2004-08-31 | Tripeptidos inhibidores de la hepatitis c con absorcion oral mejorada y composiciones farmaceuticas que los contienen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002369970A CA2369970A1 (en) | 2002-02-01 | 2002-02-01 | Hepatitis c inhibitor tri-peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2369970A1 true CA2369970A1 (en) | 2003-08-01 |
Family
ID=27626567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002369970A Abandoned CA2369970A1 (en) | 2002-02-01 | 2002-02-01 | Hepatitis c inhibitor tri-peptides |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US20030191067A1 (enExample) |
| EP (1) | EP1474423B1 (enExample) |
| JP (1) | JP4073872B2 (enExample) |
| KR (1) | KR20040081167A (enExample) |
| CN (1) | CN1304416C (enExample) |
| AR (1) | AR038382A1 (enExample) |
| AT (1) | ATE369364T1 (enExample) |
| AU (1) | AU2003202348B2 (enExample) |
| BR (1) | BR0307517A (enExample) |
| CA (1) | CA2369970A1 (enExample) |
| CO (1) | CO5611112A2 (enExample) |
| DE (1) | DE60315420T2 (enExample) |
| EA (1) | EA007739B1 (enExample) |
| EC (1) | ECSP045224A (enExample) |
| ES (1) | ES2290425T3 (enExample) |
| HR (1) | HRP20040696A2 (enExample) |
| MX (1) | MXPA04007446A (enExample) |
| MY (1) | MY133719A (enExample) |
| NO (1) | NO326421B1 (enExample) |
| NZ (1) | NZ534730A (enExample) |
| PE (1) | PE20030854A1 (enExample) |
| PL (1) | PL371283A1 (enExample) |
| RS (1) | RS67104A (enExample) |
| SA (1) | SA03240006B1 (enExample) |
| TW (1) | TWI274056B (enExample) |
| UA (1) | UA77757C2 (enExample) |
| UY (1) | UY27638A1 (enExample) |
| WO (1) | WO2003064416A1 (enExample) |
| ZA (1) | ZA200406014B (enExample) |
Families Citing this family (146)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA001915B1 (ru) | 1996-10-18 | 2001-10-22 | Вертекс Фармасьютикалз Инкорпорейтед | Ингибиторы серин-протеаз, в частности ns3 протеазы вируса гепатита c (hvc) |
| SV2003000617A (es) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
| JP3889708B2 (ja) | 2000-11-20 | 2007-03-07 | ブリストル−マイヤーズ スクイブ カンパニー | Ｃ型肝炎トリペプチド阻害剤 |
| US6867185B2 (en) | 2001-12-20 | 2005-03-15 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| WO2004043339A2 (en) | 2002-05-20 | 2004-05-27 | Bristol-Myers Squibb Company | Substituted cycloalkyl p1' hepatitis c virus inhibitors |
| ES2350201T3 (es) | 2002-05-20 | 2011-01-20 | Bristol-Myers Squibb Company | Sulfamidas heterocíclicas como inhibidores del virus de la hepatitis c. |
| PL215228B1 (pl) | 2002-05-20 | 2013-11-29 | Bristol Myers Squibb Co | Zwiazki tripeptydowe, ich zastosowanie i kompozycja farmaceutyczna je zawierajaca oraz jej zastosowanie |
| WO2004101605A1 (en) * | 2003-03-05 | 2004-11-25 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibiting compounds |
| CA2516018C (en) * | 2003-03-05 | 2011-08-23 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| US7176208B2 (en) | 2003-04-18 | 2007-02-13 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
| EP1654261B1 (en) * | 2003-05-21 | 2007-11-14 | Boehringer Ingelheim International GmbH | Hepatitis c inhibitor compounds |
| TW201127828A (en) | 2003-09-05 | 2011-08-16 | Vertex Pharma | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
| DE602004031645D1 (de) | 2003-09-22 | 2011-04-14 | Boehringer Ingelheim Pharma | Makrozyklische peptide mit wirkung gegen das hepatitis-c-virus |
| PT1670448E (pt) * | 2003-09-30 | 2008-02-11 | Tibotec Pharm Ltd | Sulfonamidas inibidoras de hcv |
| CA2541634A1 (en) * | 2003-10-10 | 2005-04-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
| US7491794B2 (en) * | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
| RS20060259A (sr) | 2003-10-14 | 2008-08-07 | Intermune Inc., | Makrociklične karboksilne kiseline i acilsulfonamidi kao inhibitori replikacije hcv |
| EP1944042A1 (en) | 2003-10-27 | 2008-07-16 | Vertex Pharmceuticals Incorporated | Combinations for HCV treatment |
| WO2005043118A2 (en) | 2003-10-27 | 2005-05-12 | Vertex Pharmaceuticals Incorporated | Drug discovery method |
| US7132504B2 (en) | 2003-11-12 | 2006-11-07 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7309708B2 (en) | 2003-11-20 | 2007-12-18 | Birstol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7135462B2 (en) | 2003-11-20 | 2006-11-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2005070955A1 (en) | 2004-01-21 | 2005-08-04 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis c virus |
| HRP20100048T1 (hr) | 2004-01-30 | 2010-04-30 | Medivir Ab | Inhibitori hcv ns-3 serin proteaze |
| UY28758A1 (es) | 2004-02-20 | 2005-09-30 | Boehringer Ingelheim Int | Inhibidores de polimerasa viral |
| CA2560897C (en) * | 2004-03-30 | 2012-06-12 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
| US7705146B2 (en) | 2004-06-28 | 2010-04-27 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor peptide analogs |
| US20080311077A1 (en) * | 2004-07-16 | 2008-12-18 | Kleem Chaudhary | Antiviral Compounds |
| WO2006007708A1 (en) * | 2004-07-20 | 2006-01-26 | Boehringer Engelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| UY29016A1 (es) * | 2004-07-20 | 2006-02-24 | Boehringer Ingelheim Int | Analogos de dipeptidos inhibidores de la hepatitis c |
| AU2005291918A1 (en) * | 2004-10-01 | 2006-04-13 | Vertex Pharmaceuticals Incorporated | HCV NS3-NS4A protease inhibition |
| TW201424733A (zh) | 2004-10-29 | 2014-07-01 | Vertex Pharma | 劑量型式 |
| US7323447B2 (en) | 2005-02-08 | 2008-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7592336B2 (en) | 2005-05-10 | 2009-09-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7608592B2 (en) | 2005-06-30 | 2009-10-27 | Virobay, Inc. | HCV inhibitors |
| US7601686B2 (en) | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TWI389908B (zh) * | 2005-07-14 | 2013-03-21 | Gilead Sciences Inc | 抗病毒化合物類 |
| EP2305697A3 (en) | 2005-07-25 | 2011-07-27 | Intermune, Inc. | Macrocyclic inhibitors of Hepatitis C virus replication |
| PE20070211A1 (es) | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| JP5015154B2 (ja) | 2005-08-12 | 2012-08-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ウイルスポリメラーゼインヒビター |
| US7964624B1 (en) | 2005-08-26 | 2011-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
| AR055395A1 (es) | 2005-08-26 | 2007-08-22 | Vertex Pharma | Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c |
| CA2624333A1 (en) | 2005-10-11 | 2007-04-19 | Intermune, Inc. | Compounds and methods for inhibiting hepatitis c viral replication |
| US7772183B2 (en) | 2005-10-12 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| US8039475B2 (en) | 2006-02-27 | 2011-10-18 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
| KR20080112303A (ko) | 2006-03-16 | 2008-12-24 | 버텍스 파마슈티칼스 인코포레이티드 | 중수소화 ｃ형 간염 프로테아제 억제제 |
| RU2008152171A (ru) | 2006-07-05 | 2010-08-10 | Интермьюн, Инк. (Us) | Новые ингибиторы вирусной репликации гепатита с |
| EP2049474B1 (en) | 2006-07-11 | 2015-11-04 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP1886685A1 (en) | 2006-08-11 | 2008-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition |
| JP2010500978A (ja) | 2006-08-17 | 2010-01-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ウイルスポリメラーゼインヒビター |
| US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2008070358A2 (en) * | 2006-11-16 | 2008-06-12 | Phenomix Corporation | N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain |
| EA200970806A1 (ru) | 2007-02-27 | 2010-08-30 | Вертекс Фармасьютикалз Инкорпорейтед | Сокристаллы и содержащие их фармацевтические композиции |
| NZ579295A (en) | 2007-02-27 | 2012-03-30 | Vertex Pharma | Inhibitors of serine proteases |
| US7932277B2 (en) * | 2007-05-10 | 2011-04-26 | Intermune, Inc. | Peptide inhibitors of hepatitis C virus replication |
| CN101790524B (zh) | 2007-06-29 | 2014-07-16 | 吉里德科学公司 | 抗病毒化合物 |
| BRPI0813733A2 (pt) * | 2007-06-29 | 2019-11-05 | Gilead Sciences Inc | composto com atividade inibidora de hcv, sua composição farmacêutica e seu uso. |
| US20090047252A1 (en) * | 2007-06-29 | 2009-02-19 | Gilead Sciences, Inc. | Antiviral compounds |
| WO2009018657A1 (en) | 2007-08-03 | 2009-02-12 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| WO2009032198A1 (en) | 2007-08-30 | 2009-03-12 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
| CA2708150A1 (en) | 2007-12-05 | 2009-06-18 | Enanta Pharmaceuticals, Inc. | Fluorinated tripeptide hcv serine protease inhibitors |
| CN103483251A (zh) | 2007-12-19 | 2014-01-01 | 贝林格尔.英格海姆国际有限公司 | 病毒聚合酶抑制剂 |
| US8202996B2 (en) | 2007-12-21 | 2012-06-19 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
| NZ587133A (en) | 2008-02-04 | 2012-10-26 | Idenix Pharmaceuticals Inc | Macrocyclic serine protease inhibitor compounds for treating an HCV infection |
| WO2009100225A1 (en) * | 2008-02-07 | 2009-08-13 | Virobay, Inc. | Inhibitors of cathepsin b |
| US8048862B2 (en) | 2008-04-15 | 2011-11-01 | Intermune, Inc. | Macrocyclic inhibitors of hepatitis C virus replication |
| US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| CN102177172A (zh) | 2008-07-02 | 2011-09-07 | 埃迪尼克斯医药公司 | 用于治疗病毒感染的化合物和药物组合物 |
| US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
| UY32099A (es) | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
| US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TW201034663A (en) * | 2008-12-19 | 2010-10-01 | Gilead Sciences Inc | HCV NS3 protease inhibitors |
| CA2750227A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
| EP2396028A2 (en) | 2009-02-12 | 2011-12-21 | Vertex Pharmceuticals Incorporated | Hcv combination therapies comprising pegylated interferon, ribavirin and telaprevir |
| AR075584A1 (es) | 2009-02-27 | 2011-04-20 | Intermune Inc | COMPOSICIONES TERAPEUTICAS QUE COMPRENDEN beta-D-2'-DESOXI-2'-FLUORO-2'-C-METILCITIDINA Y UN DERIVADO DE ACIDO ISOINDOL CARBOXILICO Y SUS USOS. COMPUESTO. |
| JP5690286B2 (ja) | 2009-03-04 | 2015-03-25 | イデニク プハルマセウティカルス，インコーポレイテッド | ホスホチオフェン及びホスホチアゾールｈｃｖポリメラーゼ阻害剤 |
| CA2758072A1 (en) | 2009-04-08 | 2010-10-14 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
| MX2011012155A (es) | 2009-05-13 | 2012-02-28 | Enanta Pharm Inc | Compuestos macrociclicos como inhibidores del virus de hepatitis c. |
| CA2769652A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
| WO2011063076A1 (en) | 2009-11-19 | 2011-05-26 | Itherx Pharmaceuticals, Inc. | Methods of treating hepatitis c virus with oxoacetamide compounds |
| NZ600608A (en) | 2009-12-18 | 2015-01-30 | Idenix Pharmaceuticals Inc | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
| EP2528605A1 (en) | 2010-01-29 | 2012-12-05 | Vertex Pharmaceuticals Incorporated | Therapies for treating hepatitis c virus infection |
| AR094621A1 (es) | 2010-04-01 | 2015-08-19 | Idenix Pharmaceuticals Inc | Compuestos y composiciones farmacéuticas para el tratamiento de infecciones virales |
| WO2011156545A1 (en) | 2010-06-09 | 2011-12-15 | Vertex Pharmaceuticals Incorporated | Viral dynamic model for hcv combination therapy |
| WO2012009503A1 (en) | 2010-07-14 | 2012-01-19 | Vertex Pharmaceuticals Incorporated | Palatable pharmaceutical composition comprising vx-950 |
| EA029145B1 (ru) | 2010-09-21 | 2018-02-28 | Энанта Фармасьютикалз, Инк. | Ингибиторы hcv сериновой протеазы, полученные из макроциклического пролина |
| CN103534256B (zh) | 2010-12-30 | 2016-08-10 | 益安药业 | 大环丙型肝炎丝氨酸蛋白酶抑制剂 |
| US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
| TW201309690A (zh) | 2011-02-10 | 2013-03-01 | Idenix Pharmaceuticals Inc | 巨環絲胺酸蛋白酶抑制劑，其醫藥組合物及其於治療ｈｃｖ感染之用途 |
| WO2012107589A1 (en) | 2011-02-11 | 2012-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment and prevention of hcv infections |
| WO2012109646A1 (en) | 2011-02-11 | 2012-08-16 | Vertex Pharmaceuticals Incorporated | Treatment of hcv in hiv infection patients |
| US20120252721A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
| US9243025B2 (en) | 2011-03-31 | 2016-01-26 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
| US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EP2755983B1 (en) | 2011-09-12 | 2017-03-15 | Idenix Pharmaceuticals LLC. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
| WO2013039855A1 (en) | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US8507460B2 (en) | 2011-10-14 | 2013-08-13 | Idenix Pharmaceuticals, Inc. | Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
| US9089574B2 (en) | 2011-11-30 | 2015-07-28 | Emory University | Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections |
| WO2013116339A1 (en) | 2012-01-31 | 2013-08-08 | Vertex Pharmaceuticals Incorporated | High potency formulations of vx-950 |
| US20130217644A1 (en) | 2012-02-13 | 2013-08-22 | Idenix Pharmaceuticals, Inc. | Pharmaceutical Compositions of 2'-C-Methyl-Guanosine, 5'-[2[(3-Hydroxy-2,2-Dimethyl-1-Oxopropyl)Thio]Ethyl N-(Phenylmethyl)Phosphoramidate] |
| JP6165848B2 (ja) | 2012-05-22 | 2017-07-19 | イデニク ファーマシューティカルズ エルエルシー | 肝疾患のためのｄ−アミノ酸化合物 |
| WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
| WO2013177195A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphate prodrugs for hcv infection |
| HK1207647A1 (en) | 2012-10-08 | 2016-02-05 | Idenix Pharmaceuticals Llc | 2'-chloro nucleoside analogs for hcv infection |
| DK2909205T3 (en) | 2012-10-19 | 2017-03-06 | Bristol Myers Squibb Co | 9-METHYL-SUBSTITUTED HEXADECAHYDROCYCLOPROPA (E) PYRROL (1,2-A) (1,4) DIAZOCYCLOPENTADECINYLCARBAMATE DERIVATIVES AS NON-STRUCTURAL 3 (NS3) PROTEASE INHIBITORS FOR TREATMENT |
| EP2909223B1 (en) | 2012-10-19 | 2017-03-22 | Idenix Pharmaceuticals LLC | Dinucleotide compounds for hcv infection |
| WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
| US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2014070964A1 (en) | 2012-11-02 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2014070974A1 (en) | 2012-11-05 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
| WO2014078436A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of sp-nucleoside analog |
| WO2014099941A1 (en) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
| ES2831625T3 (es) | 2013-02-20 | 2021-06-09 | Kala Pharmaceuticals Inc | Compuestos terapéuticos y sus usos |
| WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
| US9339541B2 (en) | 2013-03-04 | 2016-05-17 | Merck Sharp & Dohme Corp. | Thiophosphate nucleosides for the treatment of HCV |
| EP2964664B1 (en) | 2013-03-07 | 2017-01-11 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
| EP3004130B1 (en) | 2013-06-05 | 2019-08-07 | Idenix Pharmaceuticals LLC. | 1',4'-thio nucleosides for the treatment of hcv |
| EP3027636B1 (en) | 2013-08-01 | 2022-01-05 | Idenix Pharmaceuticals LLC | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
| WO2015042375A1 (en) | 2013-09-20 | 2015-03-26 | Idenix Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
| WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
| EP3063165A1 (en) | 2013-11-01 | 2016-09-07 | Idenix Pharmaceuticals LLC | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
| EP3074399A1 (en) | 2013-11-27 | 2016-10-05 | Idenix Pharmaceuticals LLC | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
| EP3083654A1 (en) | 2013-12-18 | 2016-10-26 | Idenix Pharmaceuticals LLC | 4'-or nucleosides for the treatment of hcv |
| WO2015103490A1 (en) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Solid antiviral dosage forms |
| US20170066779A1 (en) | 2014-03-05 | 2017-03-09 | Idenix Pharmaceuticals Llc | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
| WO2015134780A1 (en) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Solid prodrug forms of 2'-chloro-2'-methyl uridine for hcv |
| US20170135990A1 (en) | 2014-03-05 | 2017-05-18 | Idenix Pharmaceuticals Llc | Pharmaceutical compositions comprising a 5,5-fused heteroarylene flaviviridae inhibitor and their use for treating or preventing flaviviridae infection |
| WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
| RU2650610C1 (ru) * | 2017-02-28 | 2018-04-16 | Васильевич Иващенко Александр | Противовирусная композиция и способ ее применения |
| US12083099B2 (en) | 2020-10-28 | 2024-09-10 | Accencio LLC | Methods of treating symptoms of coronavirus infection with viral protease inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6323180B1 (en) * | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| UA74546C2 (en) * | 1999-04-06 | 2006-01-16 | Boehringer Ingelheim Ca Ltd | Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition |
-
2002
- 2002-02-01 CA CA002369970A patent/CA2369970A1/en not_active Abandoned
- 2002-12-17 US US10/320,979 patent/US20030191067A1/en not_active Abandoned
-
2003
- 2003-01-24 CN CNB038061619A patent/CN1304416C/zh not_active Expired - Fee Related
- 2003-01-24 PL PL03371283A patent/PL371283A1/xx not_active Application Discontinuation
- 2003-01-24 MX MXPA04007446A patent/MXPA04007446A/es active IP Right Grant
- 2003-01-24 DE DE60315420T patent/DE60315420T2/de not_active Expired - Lifetime
- 2003-01-24 AT AT03700745T patent/ATE369364T1/de active
- 2003-01-24 UA UA20040807171A patent/UA77757C2/uk unknown
- 2003-01-24 NZ NZ534730A patent/NZ534730A/en not_active IP Right Cessation
- 2003-01-24 BR BR0307517-6A patent/BR0307517A/pt not_active IP Right Cessation
- 2003-01-24 EA EA200400986A patent/EA007739B1/ru not_active IP Right Cessation
- 2003-01-24 ES ES03700745T patent/ES2290425T3/es not_active Expired - Lifetime
- 2003-01-24 EP EP03700745A patent/EP1474423B1/en not_active Expired - Lifetime
- 2003-01-24 AU AU2003202348A patent/AU2003202348B2/en not_active Ceased
- 2003-01-24 WO PCT/CA2003/000091 patent/WO2003064416A1/en not_active Ceased
- 2003-01-24 JP JP2003564039A patent/JP4073872B2/ja not_active Expired - Fee Related
- 2003-01-24 KR KR10-2004-7011888A patent/KR20040081167A/ko not_active Abandoned
- 2003-01-24 RS YU67104A patent/RS67104A/sr unknown
- 2003-01-24 HR HR20040696A patent/HRP20040696A2/hr not_active Application Discontinuation
- 2003-01-30 TW TW092102240A patent/TWI274056B/zh active
- 2003-01-30 PE PE2003000105A patent/PE20030854A1/es not_active Application Discontinuation
- 2003-01-30 MY MYPI20030338A patent/MY133719A/en unknown
- 2003-01-31 AR ARP030100291A patent/AR038382A1/es unknown
- 2003-01-31 UY UY27638A patent/UY27638A1/es not_active Application Discontinuation
- 2003-03-05 SA SA03240006A patent/SA03240006B1/ar unknown
-
2004
- 2004-07-28 ZA ZA200406014A patent/ZA200406014B/en unknown
- 2004-08-09 EC EC2004005224A patent/ECSP045224A/es unknown
- 2004-08-31 NO NO20043642A patent/NO326421B1/no not_active IP Right Cessation
- 2004-08-31 CO CO04085343A patent/CO5611112A2/es not_active Application Discontinuation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2369970A1 (en) | Hepatitis c inhibitor tri-peptides | |
| CA2445938C (en) | Hepatitis c inhibitor tri-peptides | |
| EP1105422B1 (en) | Hepatitis c inhibitor peptides | |
| JP4675332B2 (ja) | Ｃ型肝炎ウイルスインヒビター | |
| JP4312711B2 (ja) | ヘテロ環式スルホンアミドｃ型肝炎ウイルス阻害剤 | |
| CA2370396A1 (en) | Hepatitis c inhibitor tri-peptides | |
| JP2007534636A (ja) | Ｃ型肝炎ウイルスインヒビター | |
| CA2370400A1 (en) | Hepatitis c inhibitor tri-peptides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |