Article pubs.acs.org/jmc
Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical Compound 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, and Jill Walker GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States
ABSTRACT: 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-7azaspiro[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.
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Table 1. Potencies of 1−6b in gt1a and gt1b Replicon Assaysa
INTRODUCTION Hepatitis C virus (HCV) affects more than 170 million individuals worldwide.1 About 80% of all HCV infections become chronic and can lead to fibrosis, cirrhosis, and hepatocellular carcinoma.2,3 Until recently, a combination of injectable peginterferon and oral ribavirin had been the standard of care for the treatment of HCV infection. The use of interferon can cause unpleasant flulike symptoms and fatigue, resulting in significant treatment discontinuations and failure. The recently introduced HCV protease inhibitors increased the sustained viral response (SVR), considered a virologic cure, for both treatmentnaive and experienced patients. In addition, rapid clinical development of other anti-HCV agents, including NS5A inhibitors, promise a tantalizing opportunity for an all-oral, non-interferon HCV therapy in the near future.4−6 Daclatasvir (BMS-790052, 6) is the first-reported NS5A inhibitor with high potency in both HCV genotype 1a (gt1a) and HCV genotype 1b (gt1b) (Table 1).7,8 In their elegant and insightful work, BMS scientists identified potent “dimeric” HCV inhibitors in the mixture of biologically active species obtained by incubating the monomeric iminothiazolidinone HCV inhibitor BMS-824 in a cell culture medium. 9 Removal of the iminothiazolidinone moiety from dimeric products resulted in potent trans-stilbene class of inhibitors,10 which through several other series11,12 led to “dimeric” biphenyl scaffold in 6.7,8 Additional NS5A inhibitors from a number of laboratories have been reported in patent and scientific literature.13−15 © 2014 American Chemical Society
replicon pEC50
a
compd
gt1a
gt1b
1 2 3 4 5 6 6a 6b
