Identification of Anthranilic Acid Derivatives as a Novel Class of Allosteric Inhibitors of Hepatitis C NS5B Polymerase
Journal of Medicinal Chemistry2007Vol. 50(9), pp. 2108–2116
Citations Over TimeTop 11% of 2007 papers
Thomas Nittoli, Kevin J. Curran, Shabana Insaf, Martin DiGrandi, Mark Orlowski, Rajiv Chopra, Atul Agarwal, Anita Y. M. Howe, Amar S. Prashad, M. Brawner Floyd, Bernard D. Johnson, Alan G. Sutherland, Karen Wheless, Boris Feld, Juliette O’Connell, Tarek S. Mansour, Jonathan D. Bloom
Abstract
A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.
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