Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876

Journal Article · Tue Jul 25 04:00:00 EDT 2017 · ChemMedChem(Print)

DOI:https://doi.org/10.1002/cmdc.201700228· OSTI ID:1404969

McComas, Casey C. ^[1]; Palani, Anandan ^[1]; Chang, Wei ^[2]; Holloway, M. Katharine ^[1]; Lesburg, Charles A. ^[1]; Li, Peng ^[2]; Liverton, Nigel ^[1]; Meinke, Peter T. ^[1]; Olsen, David B. ^[1]; Peng, Xuanjia ^[2]; Soll, Richard M. ^[2]; Ummat, Ajay ^[1]; Wu, Jie ^[2]; Wu, Jin ^[1]; Zorn, Nicolas ^[1]; Ludmerer, Steven W. ^[1]

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1. Merck & Co. Inc., Kenilworth NJ USA; Present address: International Discovery Service Unit, WuXi AppTec, Inc., 1690 Sumneytown Pike, Suite 150 Lansdale PA 19446 USA
2. WuXi AppTec, Shanghai China

Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1404969
• Journal Information: ChemMedChem(Print), Journal Name: ChemMedChem(Print) Journal Issue: 17 Vol. 12; ISSN 1860-7179
• Publisher: ChemPubSoc Europe
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES