Inhibitors of hepatitis C virus polymerase: Synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzam ides

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 7; pp. 2119 - 2124
• Main Authors: Cheng, Cliff C, Shipps, Gerald W, Yang, Zhiwei, Kawahata, Noriyuki, Lesburg, Charles A, Duca, Jose S, Bandouveres, Jamie, Bracken, Jack D, Jiang, Chuan-Kui, Agrawal, Sony, Ferrari, Eric, Huang, H-C
• Format: Journal Article
• Language: English
• Published: 01.04.2010
• Subjects: Antibodies; Hepatitis C virus
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.02.054

SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phen ylpropan-2-ylamino)-2-oxoethoxy)benzamide ( 1), identified using our proprietary automated ligand identification system (ALIS), super(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoeth oxy)-N-isopentyl-N-methylbenzamidecarboxamide ( 41) (IC sub(50) = 0.5 kM). The crystal structure of an analogue ( 44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase. AB: