Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound

…, M Duan, S Baskaran, J Botyanszki…

Index: Kazmierski, Wieslaw M.; Maynard, Andrew; Duan, Maosheng; Baskaran, Sam; Botyanszki, Janos; Crosby, Renae; Dickerson, Scott; Tallant, Matthew; Grimes, Rick; Hamatake, Robert; Leivers, Martin; Roberts, Christopher D.; Walker, Jill Journal of Medicinal Chemistry, 2014 , vol. 57, # 5 p. 2058 - 2073

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Citation Number: 22

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 ...