Discovery of the First C-Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients
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- 作者：Aesop Cho ; Lijun Zhang ; Jie Xu ; Rick Lee ; Thomas Butler ; Sammy Metobo ; Vangelis Aktoudianakis ; Willard Lew ; Hong Ye ; Michael Clarke ; Edward Doerffler ; Daniel Byun ; Ting Wang ; Darius Babusis ; Anne C. Carey ; Polina German ; Dorothea Sauer ; Weidong Zhong ; Stephen Rossi ; Martijn Fenaux ; John G. McHutchison ; Jason Perry ; Joy Feng ; Adrian S. Ray ; Choung U. Kim
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 13, 2014
- 年：2014
- 卷：57
- 期：5
- 页码：1812-1825
- 全文大小：546K
- 年卷期：v.57,no.5(March 13, 2014)
- ISSN：1520-4804
文摘
Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1鈥?cyano-2鈥?C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.