The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A detailed account of the progression from early C2-symmetrical compounds with unfavorable genotype 1a potencies to non-symmetrical compounds with high potencies for both genotype 1a and 1b is presented. Additionally, a novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6  ) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity-relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20  , with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 pM and 8 pM against genotype 1a and 1b replicons, respectively.

Discovery of thienoimidazole-based HCV NS5A genotype 1a and 1b inhibitors

248th National Meeting (2014)

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