Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase

We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.

Graphical abstractThe evolutionary path is reported to conformationally constrained indole inhibitors of HCV NS5B-polymerase. Biochemical and cell-based potency was achieved, coupled with attractive DMPK properties—leading ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.Figure optionsDownload full-size imageDownload as PowerPoint slide