CN102099353A - 丙型肝炎病毒抑制剂 - Google Patents
丙型肝炎病毒抑制剂 Download PDFInfo
- Publication number
- CN102099353A CN102099353A CN2009801276783A CN200980127678A CN102099353A CN 102099353 A CN102099353 A CN 102099353A CN 2009801276783 A CN2009801276783 A CN 2009801276783A CN 200980127678 A CN200980127678 A CN 200980127678A CN 102099353 A CN102099353 A CN 102099353A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- carbonyl
- cycloalkyl
- heterocyclic radical
- 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.)
- Pending
Links
- 241000711549 Hepacivirus C Species 0.000 title abstract description 89
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 239000000203 mixture Substances 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 154
- -1 cyano group alkyl Chemical group 0.000 claims description 105
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 92
- 125000003118 aryl group Chemical group 0.000 claims description 84
- 125000003545 alkoxy group Chemical group 0.000 claims description 82
- 150000003839 salts Chemical class 0.000 claims description 64
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 55
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 45
- 125000004122 cyclic group Chemical group 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 44
- 125000001188 haloalkyl group Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 32
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 230000000694 effects Effects 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 24
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 20
- 108010047761 Interferon-alpha Proteins 0.000 claims description 16
- 102000006992 Interferon-alpha Human genes 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 15
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 102000014150 Interferons Human genes 0.000 claims description 13
- 108010050904 Interferons Proteins 0.000 claims description 13
- 239000005864 Sulphur Substances 0.000 claims description 13
- 229940079322 interferon Drugs 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 11
- 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 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229960000329 ribavirin Drugs 0.000 claims description 10
- 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 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 8
- 108010022999 Serine Proteases Proteins 0.000 claims description 8
- 102000012479 Serine Proteases Human genes 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 101800001019 Non-structural protein 4B Proteins 0.000 claims description 6
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 102000005741 Metalloproteases Human genes 0.000 claims description 5
- 108010006035 Metalloproteases Proteins 0.000 claims description 5
- 108060004795 Methyltransferase Proteins 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000011161 development Methods 0.000 claims description 5
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004032 5'-inosinyl group Chemical group 0.000 claims description 4
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 claims description 4
- 229930010555 Inosine Natural products 0.000 claims description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 4
- 101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 claims description 4
- 102100040018 Interferon alpha-2 Human genes 0.000 claims description 4
- 108010079944 Interferon-alpha2b Proteins 0.000 claims description 4
- 102000013462 Interleukin-12 Human genes 0.000 claims description 4
- 108010065805 Interleukin-12 Proteins 0.000 claims description 4
- 102000000588 Interleukin-2 Human genes 0.000 claims description 4
- 108010002350 Interleukin-2 Proteins 0.000 claims description 4
- 102000004889 Interleukin-6 Human genes 0.000 claims description 4
- 108090001005 Interleukin-6 Proteins 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
- 229960003805 amantadine Drugs 0.000 claims description 4
- 210000002443 helper t lymphocyte Anatomy 0.000 claims description 4
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 claims description 4
- 229960002751 imiquimod Drugs 0.000 claims description 4
- 229960003786 inosine Drugs 0.000 claims description 4
- 230000002452 interceptive effect Effects 0.000 claims description 4
- 229940117681 interleukin-12 Drugs 0.000 claims description 4
- 229940100601 interleukin-6 Drugs 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 229960000888 rimantadine Drugs 0.000 claims description 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000047 product Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 101710144111 Non-structural protein 3 Proteins 0.000 description 38
- 102000035195 Peptidases Human genes 0.000 description 38
- 108091005804 Peptidases Proteins 0.000 description 38
- 238000005406 washing Methods 0.000 description 37
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 239000002585 base Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 150000002431 hydrogen Chemical class 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000005336 cracking Methods 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000012530 fluid Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 238000013016 damping Methods 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000000284 extract Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 14
- 235000001014 amino acid Nutrition 0.000 description 14
- 150000001413 amino acids Chemical group 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 239000000825 pharmaceutical preparation Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 229910004298 SiO 2 Inorganic materials 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- 238000001802 infusion Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 108060001084 Luciferase Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 9
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Natural products CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 230000002363 herbicidal effect Effects 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 229920002554 vinyl polymer Polymers 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000002674 ointment Substances 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- 101800001020 Non-structural protein 4A Proteins 0.000 description 6
- 239000004365 Protease Substances 0.000 description 6
- 239000002299 complementary DNA Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 235000019419 proteases Nutrition 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010057248 Cell death Diseases 0.000 description 4
- 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 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 4
- 238000007738 vacuum evaporation Methods 0.000 description 4
- CCXQVBSQUQCEEO-UHFFFAOYSA-N 1-bromobutan-2-one Chemical compound CCC(=O)CBr CCXQVBSQUQCEEO-UHFFFAOYSA-N 0.000 description 3
- RITCJGIGTNSDKO-UHFFFAOYSA-N 2-ethenylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1CC1C=C RITCJGIGTNSDKO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 238000006418 Brown reaction Methods 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- 241000710781 Flaviviridae Species 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 108010076039 Polyproteins Proteins 0.000 description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 150000001502 aryl halides Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 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
- 125000004185 ester group Chemical group 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000002797 proteolythic effect Effects 0.000 description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- RFAQWADNTLIWMG-RDDDGLTNSA-N (1r,2s)-2-ethenyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N[C@]1(C(O)=O)C[C@H]1C=C RFAQWADNTLIWMG-RDDDGLTNSA-N 0.000 description 2
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 2
- GALLMPFNVWUCGD-UHFFFAOYSA-N 1-azaniumyl-2-ethenylcyclopropane-1-carboxylate Chemical compound OC(=O)C1(N)CC1C=C GALLMPFNVWUCGD-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 2
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000710188 Encephalomyocarditis virus Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- IFQSXNOEEPCSLW-DKWTVANSSA-N L-cysteine hydrochloride Chemical compound Cl.SC[C@H](N)C(O)=O IFQSXNOEEPCSLW-DKWTVANSSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 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
- 101800001014 Non-structural protein 5A Proteins 0.000 description 2
- 241000721451 Pectinophora gossypiella Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000005001 aminoaryl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 235000019633 pungent taste Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- RGHNJXZEOKUKBD-NRXMZTRTSA-N (2r,3r,4r,5s)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-NRXMZTRTSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- JXDNUMOTWHZSCB-XMTZKCFKSA-N (3s)-3-acetamido-4-[[(2s)-3-carboxy-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1r)-1-carboxy-2-sulfanylethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(O)=O JXDNUMOTWHZSCB-XMTZKCFKSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 0 *c1c(cccc2)c2ccn1 Chemical compound *c1c(cccc2)c2ccn1 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- USBRBYCPDQGUNI-UHFFFAOYSA-N 1-chloropropane;sulfuryl dichloride Chemical compound CCCCl.ClS(Cl)(=O)=O USBRBYCPDQGUNI-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- FMYBFLOWKQRBST-UHFFFAOYSA-N 2-[bis(carboxymethyl)amino]acetic acid;nickel Chemical compound [Ni].OC(=O)CN(CC(O)=O)CC(O)=O FMYBFLOWKQRBST-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- VMVZMFMKKYTBEF-UHFFFAOYSA-N 2-aminoethanol tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.NCCO VMVZMFMKKYTBEF-UHFFFAOYSA-N 0.000 description 1
- RFAQWADNTLIWMG-UHFFFAOYSA-N 2-ethenyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1(C(O)=O)CC1C=C RFAQWADNTLIWMG-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GPKDGVXBXQTHRY-UHFFFAOYSA-N 3-chloropropane-1-sulfonyl chloride Chemical compound ClCCCS(Cl)(=O)=O GPKDGVXBXQTHRY-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- QEDXSHCYPROEOK-UHFFFAOYSA-N 3-phosphanylpropanoic acid Chemical class OC(=O)CCP QEDXSHCYPROEOK-UHFFFAOYSA-N 0.000 description 1
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- SJQRQOKXQKVJGJ-UHFFFAOYSA-N 5-(2-aminoethylamino)naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(NCCN)=CC=CC2=C1S(O)(=O)=O SJQRQOKXQKVJGJ-UHFFFAOYSA-N 0.000 description 1
- KUXKWCPBFHIJJJ-UHFFFAOYSA-N 6-hydroxy-2-methylhex-2-enoic acid Chemical compound OC(=O)C(C)=CCCCO KUXKWCPBFHIJJJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100024630 Asc-type amino acid transporter 1 Human genes 0.000 description 1
- 241001328122 Bacillus clausii Species 0.000 description 1
- 241000006382 Bacillus halodurans Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 description 1
- XYKGYSLZRUDANB-KGUYNWRUSA-N CC(C)C(C(N(C[C@@H](C1)OC(N(Cc2ccc3)Cc2c3F)=O)[C@@H]1C(N[C@](C1)([C@@H]1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)Nc1cc(C)cc(C)n1 Chemical compound CC(C)C(C(N(C[C@@H](C1)OC(N(Cc2ccc3)Cc2c3F)=O)[C@@H]1C(N[C@](C1)([C@@H]1C=C)C(NS(C1CC1)(=O)=O)=O)=O)=O)Nc1cc(C)cc(C)n1 XYKGYSLZRUDANB-KGUYNWRUSA-N 0.000 description 1
- NBJXCTLFPNBZSG-UHFFFAOYSA-N CCOC(C(C1)(C1C=C)N)=O Chemical compound CCOC(C(C1)(C1C=C)N)=O NBJXCTLFPNBZSG-UHFFFAOYSA-N 0.000 description 1
- MUWAMLYKLZSGPE-UHFFFAOYSA-N CCOC(C(C1)(C1C=C)NC(OC(C)(C)C)=O)=O Chemical compound CCOC(C(C1)(C1C=C)NC(OC(C)(C)C)=O)=O MUWAMLYKLZSGPE-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 235000019750 Crude protein Nutrition 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000016559 DNA Primase Human genes 0.000 description 1
- 108010092681 DNA Primase Proteins 0.000 description 1
- 101710118188 DNA-binding protein HU-alpha Proteins 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100364969 Dictyostelium discoideum scai gene Proteins 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010025815 Kanamycin Kinase Proteins 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100364971 Mus musculus Scai gene Proteins 0.000 description 1
- 108010064696 N,O-diacetylmuramidase Proteins 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 101710144128 Non-structural protein 2 Proteins 0.000 description 1
- 101710199667 Nuclear export protein Proteins 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 229930182556 Polyacetal Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 101150081875 Slc7a10 gene Proteins 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 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
- DIWWAUHOTDSZEV-UHFFFAOYSA-N [Cl].S(=O)(=O)(N)N Chemical compound [Cl].S(=O)(=O)(N)N DIWWAUHOTDSZEV-UHFFFAOYSA-N 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 150000001501 aryl fluorides Chemical class 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 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
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DLTBAYKGXREKMW-UHFFFAOYSA-N cyclopropanesulfonic acid Chemical compound OS(=O)(=O)C1CC1 DLTBAYKGXREKMW-UHFFFAOYSA-N 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940089256 fungistat Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000001683 mentha spicata herb oil Substances 0.000 description 1
- 108010003855 mesentericopeptidase Proteins 0.000 description 1
- 150000001457 metallic cations Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 108010020132 microbial serine proteinases Proteins 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- SPGDRXRIVPMUCK-UHFFFAOYSA-N n-tert-butyl-3-chloropropane-1-sulfonamide Chemical compound CC(C)(C)NS(=O)(=O)CCCCl SPGDRXRIVPMUCK-UHFFFAOYSA-N 0.000 description 1
- JTZIZFSBVOHJQD-UHFFFAOYSA-N n-tert-butylcyclopropanesulfonamide Chemical class CC(C)(C)NS(=O)(=O)C1CC1 JTZIZFSBVOHJQD-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- LYRFLYHAGKPMFH-UHFFFAOYSA-N octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(N)=O LYRFLYHAGKPMFH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 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
- 229940100611 topical cream Drugs 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 210000000605 viral structure Anatomy 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5347708P | 2008-05-15 | 2008-05-15 | |
| US61/053,477 | 2008-05-15 | ||
| PCT/US2009/043920 WO2009140475A1 (en) | 2008-05-15 | 2009-05-14 | Hepatitis c virus inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102099353A true CN102099353A (zh) | 2011-06-15 |
Family
ID=41017064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801276783A Pending CN102099353A (zh) | 2008-05-15 | 2009-05-14 | 丙型肝炎病毒抑制剂 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20090285774A1 (enExample) |
| EP (1) | EP2280958A1 (enExample) |
| JP (1) | JP2011521911A (enExample) |
| CN (1) | CN102099353A (enExample) |
| WO (1) | WO2009140475A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965286A (zh) * | 2014-04-22 | 2014-08-06 | 南京安赛莱医药科技有限公司 | 丙型肝炎病毒（hcv）ns3蛋白酶抑制剂 |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2009142842A2 (en) | 2008-04-15 | 2009-11-26 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| 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 |
| 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. |
| EP2429568B1 (en) | 2009-05-13 | 2016-08-17 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
| US9193740B2 (en) * | 2009-10-19 | 2015-11-24 | Enanta Pharmaceuticals, Inc. | Bismacrocyclic compounds as hepatitis C virus inhibitors |
| EP2655362A1 (en) | 2010-12-22 | 2013-10-30 | Abbvie Inc. | Hepatitis c inhibitors and uses thereof |
| KR20140003521A (ko) | 2010-12-30 | 2014-01-09 | 이난타 파마슈티칼스, 인코포레이티드 | 페난트리딘 매크로사이클릭 ｃ형 간염 세린 프로테아제 억제제 |
| MX2013007677A (es) | 2010-12-30 | 2013-07-30 | Abbvie Inc | Inhibidores macrociclicos de serina proteasa de hepatitis. |
| 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 |
| TWI589576B (zh) | 2011-07-15 | 2017-07-01 | 諾華公司 | 氮雜－雙環二芳基醚之鹽類及製造彼等或其前驅物之方法 |
| MX355102B (es) | 2012-01-11 | 2018-04-05 | Abbvie Ireland Unlimited Co | Procesos para hacer los inhibidores de la proteasa del hcv. |
| HRP20161694T1 (hr) | 2012-10-19 | 2017-03-10 | Bristol-Myers Squibb Company | 9-metil supstituirani heksadekahidrociklopropa(e)pirolo (1,2-a)(1,4) diazaciklopentadecinil karbamat derivati kao ne-strukturalni 3 (ns3) proteazni inhibitori za liječenje infekcija virusom hepatitisa c |
| US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2014070964A1 (en) | 2012-11-02 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP2914598B1 (en) | 2012-11-02 | 2017-10-18 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2015103490A1 (en) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Solid antiviral dosage forms |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1323316A (zh) * | 1998-08-10 | 2001-11-21 | 贝林格尔·英格海姆加拿大有限公司 | 丙型肝炎三肽抑制剂 |
| WO2006000085A1 (en) * | 2004-06-28 | 2006-01-05 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| US20080032936A1 (en) * | 2006-08-04 | 2008-02-07 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl tripeptide hepatitis C virus inhibitors |
| CN101951769A (zh) * | 2007-12-21 | 2011-01-19 | 阿维拉制药公司 | Hcv蛋白酶抑制剂和其用途 |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0475255A3 (en) * | 1990-09-12 | 1993-04-14 | F. Hoffmann-La Roche Ag | Process for the preparation of optically pure (s)-alpha-((tert-butylsulfonyl)methyl)hydro cinnamic acid |
| CN100391967C (zh) * | 2000-11-20 | 2008-06-04 | 布里斯托尔-迈尔斯斯奎布公司 | 丙型肝炎三肽抑制剂 |
| MY140680A (en) * | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| US20060199773A1 (en) * | 2002-05-20 | 2006-09-07 | Sausker Justin B | Crystalline forms of (1R,2S)-N-[(1,1-dimethylethoxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(6-methoxy-1-isoquinolinyl)oxy]-L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-cyclopropanecarboxamide, monopotassium salt |
| US7601709B2 (en) * | 2003-02-07 | 2009-10-13 | Enanta Pharmaceuticals, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
| JP4733023B2 (ja) * | 2003-04-16 | 2011-07-27 | ブリストル−マイヤーズ スクイブ カンパニー | Ｃ型肝炎ウイルスの大環状イソキノリンペプチド阻害剤 |
| JP4654239B2 (ja) * | 2004-03-15 | 2011-03-16 | 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 | Ｃ型肝炎ウィルス感染症の治療に適した大環状ジペプチドの調製方法 |
| US7601686B2 (en) * | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TW200738742A (en) * | 2005-07-14 | 2007-10-16 | Gilead Sciences Inc | Antiviral compounds |
| US7825152B2 (en) * | 2006-04-11 | 2010-11-02 | Novartis Ag | Organic compounds and their uses |
| US8268776B2 (en) * | 2006-06-06 | 2012-09-18 | Enanta Pharmaceuticals, Inc. | Macrocylic oximyl hepatitis C protease inhibitors |
| US7582605B2 (en) * | 2006-08-11 | 2009-09-01 | Enanta Pharmaceuticals, Inc. | Phosphorus-containing hepatitis C serine protease inhibitors |
| US7605126B2 (en) * | 2006-08-11 | 2009-10-20 | Enanta Pharmaceuticals, Inc. | Acylaminoheteroaryl hepatitis C virus protease inhibitors |
| US7772180B2 (en) * | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US20080279821A1 (en) * | 2007-04-26 | 2008-11-13 | Deqiang Niu | Arylpiperidinyl and arylpyrrolidinyl macrocyclic hepatitis c serine protease inhibitors |
| EP2160392A2 (en) * | 2007-05-03 | 2010-03-10 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| BRPI0811447A2 (pt) * | 2007-05-10 | 2014-10-29 | Intermune Inc | Compostos, composição farmacêutica e métodos de inibição da atividade da protease ns3/ns4, de tratamento da fibrose hepática e de intensificação da função hepática num indivíduo tendo infecção de vírus da hepatite c. |
| US20090047252A1 (en) * | 2007-06-29 | 2009-02-19 | Gilead Sciences, Inc. | Antiviral compounds |
| 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 |
-
2009
- 2009-05-13 US US12/465,142 patent/US20090285774A1/en not_active Abandoned
- 2009-05-14 EP EP09747557A patent/EP2280958A1/en not_active Withdrawn
- 2009-05-14 JP JP2011509693A patent/JP2011521911A/ja active Pending
- 2009-05-14 CN CN2009801276783A patent/CN102099353A/zh active Pending
- 2009-05-14 WO PCT/US2009/043920 patent/WO2009140475A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1323316A (zh) * | 1998-08-10 | 2001-11-21 | 贝林格尔·英格海姆加拿大有限公司 | 丙型肝炎三肽抑制剂 |
| WO2006000085A1 (en) * | 2004-06-28 | 2006-01-05 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| US20080032936A1 (en) * | 2006-08-04 | 2008-02-07 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl tripeptide hepatitis C virus inhibitors |
| CN101951769A (zh) * | 2007-12-21 | 2011-01-19 | 阿维拉制药公司 | Hcv蛋白酶抑制剂和其用途 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965286A (zh) * | 2014-04-22 | 2014-08-06 | 南京安赛莱医药科技有限公司 | 丙型肝炎病毒（hcv）ns3蛋白酶抑制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009140475A1 (en) | 2009-11-19 |
| US20090285774A1 (en) | 2009-11-19 |
| EP2280958A1 (en) | 2011-02-09 |
| JP2011521911A (ja) | 2011-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102099353A (zh) | 丙型肝炎病毒抑制剂 | |
| CN102164928B (zh) | 丙型肝炎病毒抑制剂 | |
| JP4874227B2 (ja) | Ｃ型肝炎ウイルスのｎｓ３セリンプロテアーゼインヒビターとしての環状ｐ４’ｓを有する新規ケトアミド | |
| CN102317306B (zh) | 丙型肝炎病毒抑制剂 | |
| ES2328589T3 (es) | Compuestos de la prolina 3,4(ciclopentil) fusionados como inhibidores de la proteasa serina ns3 del virus de la hepatitis c. | |
| JP4745327B2 (ja) | Ｃ型肝炎ウイルスｎｓ３プロテアーゼのインヒビター | |
| EP1506172B1 (en) | Hepatitis c virus inhibitors | |
| ES2355015T3 (es) | Compuestos de azufre como inhibidores de la serina proteasa ns3 del virus de la hepatitis c. | |
| JP4525982B2 (ja) | Ｃ型肝炎ウイルスのｎｓ３セリンプロテアーゼの大環状インヒビター | |
| ES2327544T3 (es) | Compuestos novedosos como inhibidores de serina proteasa ns3 de virus de hepetitis c. | |
| CN100509784C (zh) | 丙型肝炎病毒ns3/ns4a丝氨酸蛋白酶的抑制剂 | |
| CN103936819B (zh) | 丙型肝炎病毒抑制剂 | |
| CN101189223A (zh) | 丙型肝炎病毒抑制剂 | |
| JP6110846B2 (ja) | Ｃ型肝炎ウイルス阻害剤としての重水素が導入されたトリペプチド | |
| JP2007525510A (ja) | Ｃ型肝炎ウイルスｎｓ３セリンプロテアーゼのインヒビターとしての化合物 | |
| CN102112486A (zh) | 丙型肝炎病毒抑制剂 | |
| JP2008502718A (ja) | Ｃ型肝炎ウイルスｎｓ３セリンプロテアーゼのインヒビターとしての置換型プロリン | |
| CN102307890A (zh) | 丙型肝炎病毒抑制剂 | |
| JP2011520906A (ja) | Ｃ型肝炎ウイルス阻害剤 | |
| JP2014522809A (ja) | Ｃ型肝炎ウイルス阻害剤 | |
| JP2007525521A (ja) | Ｃ型肝炎ウイルスｎｓ３セリンプロテアーゼのインヒビターとしてのシクロブテンジオン基含有化合物 | |
| CN101568336A (zh) | 大环肽作为丙型肝炎病毒抑制剂 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110615 |