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Publication Abstract from PubMed

SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylam ino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(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-oxoethoxy)-N-isop entyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). 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.

Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides.,Cheng CC, Shipps GW Jr, Yang Z, Kawahata N, Lesburg CA, Duca JS, Bandouveres J, Bracken JD, Jiang CK, Agrawal S, Ferrari E, Huang HC Bioorg Med Chem Lett. 2010 Apr 1;20(7):2119-24. Epub 2010 Feb 18. PMID:20219368^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.