The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase

The monoethyl ester of meconic acid was discovered as novel inhibitor of HCV NS5B RNA dependent RNA polymerase. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design. Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with α,γ-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.