Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical Compound
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- 作者：Wieslaw M. Kazmierski ; Andrew Maynard ; Maosheng Duan ; Sam Baskaran ; Janos Botyanszki ; Renae Crosby ; Scott Dickerson ; Matthew Tallant ; Rick Grimes ; Robert Hamatake ; Martin Leivers ; Christopher D. Roberts ; Jill Walker
- 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：2058-2073
- 全文大小：789K
- 年卷期：v.57,no.5(March 13, 2014)
- ISSN：1520-4804
文摘
Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.