Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase.
Article Details
- CitationCopy to clipboard
Nittoli T, Curran K, Insaf S, DiGrandi M, Orlowski M, Chopra R, Agarwal A, Howe AY, Prashad A, Floyd MB, Johnson B, Sutherland A, Wheless K, Feld B, O'Connell J, Mansour TS, Bloom J
Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase.
J Med Chem. 2007 May 3;50(9):2108-16. Epub 2007 Apr 3.
- PubMed ID
- 17402724 [ View in PubMed]
- 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.