From a cell-based, high throughput screen, a hit was identified that exhibited an EC50 of 0.57 �M in a HCV 1b replicon assay and for which resistance mapped to the NS5A protein. During an initial SAR investigation, it became apparent that minor dimeric derivatives of the parental compounds contributed to the antiviral activity. This observation, along with the preliminary understanding of the SAR, allowed the design of a novel stilbene-based lead that was 2300-fold more potent than the initial hit. Subsequent iterative optimization of potency and ADME properties culminated in the discovery of the highly potent analog BMS-790052 (1a/1b EC50 = 50 pM / 9 pM), currently in Phase II studies as an add-on to standard of care. Notable aspects of the lead identification effort, in vitro cell-based studies that corroborated NS5A as the likely target, and early clinical results will be discussed.

Discovery of potent HCV inhibitors targeting the NS5A protein

240th National Meeting (2010)

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