Optimization of Thienopyrrole‐Based Finger‐Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase

Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold. Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. We previously discovered allosteric inhibitors of the HCV NS5B polymerase based on a thieno[3,2‐b]pyrrole scaffold, exemplified by 4. X‐ray crystallography confirmed binding of thienopyrroles to the upper‐thumb domain of NS5B. Extensive structure–activity relationship studies around compound 4 identified the potent tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs.