| Literature DB >> 24568313 |
Wieslaw M Kazmierski1, 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.
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-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.Entities:
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Year: 2014 PMID： 24568313 DOI： 10.1021/jm4013104
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446