HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies |
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| Authors: | Omar D Lopez Van N Nguyen Denis R St Laurent Makonen Belema Michael H Serrano-Wu Jason T Goodrich Fukang Yang Yuping Qiu Amy S Ripka Peter T Nower Lourdes Valera Mengping Liu Donald R O’Boyle Jin-Hua Sun Robert A Fridell Julie A Lemm Min Gao Andrew C Good Lawrence B Snyder |
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| Institution: | 1. Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;2. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;3. Department of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA |
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| Abstract: | In a recent disclosure,1 we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC50 in a genotype 1b replicon assay. |
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