- A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus
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A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1′R,2′S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
- Yeh, Teng-Kuang,Kang, Iou-Jiun,Hsu, Tsu-An,Lee, Yen-Chun,Lee, Chung-Chi,Hsu, Sheng-Ju,Tian, Ya-Wen,Yang, Hui-Yun,Chen, Chiung-Tong,Chao, Yu-Sheng,Yueh, Andrew,Chern, Jyh-Haur
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p. 245 - 268
(2019/02/19)
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- Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors
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A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
- Dwyer, Michael P.,Keertikar, Kerry M.,Chen, Lei,Tong, Ling,Selyutin, Oleg,Nair, Anilkumar G.,Yu, Wensheng,Zhou, Guowei,Lavey, Brian J.,Yang, De-Yi,Wong, Michael,Kim, Seong Heon,Coburn, Craig A.,Rosenblum, Stuart B.,Zeng, Qingbei,Jiang, Yueheng,Shankar, Bandarpalle B.,Rizvi, Razia,Nomeir, Amin A.,Liu, Rong,Agrawal, Sony,Xia, Ellen,Kong, Rong,Zhai, Ying,Ingravallo, Paul,Asante-Appiah, Ernest,Kozlowski, Joseph A.
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p. 4106 - 4111
(2016/08/01)
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- ANTI-VIRAL COMPOUNDS
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Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
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Paragraph 0264; 0266
(2015/11/24)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 67
(2012/02/15)
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- HEPATITIS C VIRUS INHIBITORS
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This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds
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Page/Page column 217
(2012/04/10)
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- HEPATITIS C VIRUS INHIBITORS
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The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts thereof; to compositions containing such compounds; and to the of such compounds as inhibitors of HCV replication.
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Page/Page column 114
(2012/01/05)
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- HEPATITIS C VIRUS INHIBITORS
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The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts thereof, to compositions containing such compounds and to the use of such compounds as inhibitors of HCV replication.
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Page/Page column 128
(2011/02/24)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to methods for making compounds useful in the treatment of Hepatitis C virus (HCV) infection.
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Page/Page column 69
(2011/06/16)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 64
(2011/07/07)
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- Anti-Viral Compounds
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Compounds effective in inhibiting replication of Hepatitis C virus (“HCV”) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
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- HEPATITIS C VIRUS INHIBITORS
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This disclosure concerns novel compounds of Formula (I) or Formula (II) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.
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Page/Page column 121
(2010/11/04)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to (4-4' -diimidazolyl) biphenyls compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 74
(2009/10/09)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds of the following formula (I) or a pharmaceutically acceptable salt thereof, wherein A and B are each phenyl; D and E are each five-membered aromatic rings containing one, two, or three i hcteroatoms independently selected from nitrogen, oxygen, and sulfur; provided that ', at least one of D and E is other than imidazole; compositions and methods for the treatment of Hepatitis C virus (HCV) inf ection. Also disclosed are pharmaceutical compositions containing such compounds and methods f or using these compounds in the treatment of HCV inf ection.
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Page/Page column 78
(2009/01/20)
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- Hepatitis C Virus Inhibitors
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The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 48
(2008/06/13)
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- Syntheses of optically active, protected and unprotected vinylglycines
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Vinylglycine (2) has been shown to undergo racemization under acidic conditions. Optically pure 2 was obtained from 2 · HCl by enzymatic hydrolysis through N-acetylvinylglycine (5), followed by recrystallization. (S)N-(Methoxycarbonyl)vinylglycine (6) was configurationally so unstable under acidic conditions that 6 could not be obtained from 2 in an optically pure form. On the other hand, configurationally stable (S)-N-(9-phenylfluoren-9-yl)vinylglycine methyl ester (9) was synthesized from (S)-homoserine; 9 was hydrolyzed with sodium hydroxide to afford the carboxylic acid 10 of more than 99% ee.
- Itaya,Shimizu,Nakagawa,Morisue
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p. 1927 - 1930
(2007/10/02)
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