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Overview
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Background
MK-5172 is a selective inhibitor of Hepatitis C Virus NS3/4a Protease [1].Hepatitis C (HCV) virus is a member of the Flaviviridae family of viruses in the Hepacivirus genus and encoded by a 9.6-kb positive strand RNA genome [2].In biochemical assays, MK-5172 inhibited a series of major genotypes and common mutants in a HCV NS3/4A protease enzymatic assay. In a cell-based replicon system, MK-5172 inhibited HCV with EC50 values of 2 nM against genotype 1a, 0.5 nM against genotype 1b, 8 nM against genotype 2a and 13 nM against genotype 3. Also, MK-5172 is effective against HCV genotypes 1a, 2a, 1b, 2b and 3a [2].Treatment three chronically HCV-infected chimpanzees with a dose of 1 mg/kg twice daily for 7 days, Two of the chimpanzees had wild-type (WT) gt1a or gt1b infections with high viral titers (~106 IU/ml). A third chimpanzee had a modest viral titer (~104 IU/ml) that was gt1a NS3 R155K virus. MK-5172 (1 mg/kg) reduced viral titer of the gt1a (WT) infection to ~100 IU/ml within 2 days and the gt1b infection to 20 IU/ml. The gt1a NS3 R155K-infected chimp experienced a rapid ~2-log reduction in viral titer [2].
[1]. Harper S, McCauley JA, Rudd MT, et al. Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett, 2012, 3(4): 332-336.
[2]. Summa V, Ludmerer SW, McCauley JA, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother, 2012, 56(8): 4161-4167.
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