The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase

Abstract

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.

Fig. 1. Former and currently marketed HCV drugs.

Fig. 2. Alternative cores evaluated.

Fig. 3. Co-crystal structure of 5 bound to NS5B GT-2a L30S protein. Compound 5 is depicted in ball and stick representation with orange carbon atoms. Protein is shown with a green backbone cartoon and specific residues are displayed in stick representation with either green or cyan (Q414) carbon atoms. Hydrogen-bonds are denoted as black dotted lines. The omitted Fo–Fc electron density is contoured at 3 rmsd in magenta mesh. Image generated with the PyMOL molecular graphics system (v. 1.8, Schrödinger, LLC).

Fig. 4. Co-crystal structure of 5 bound to NS5B GT-1b WT protein. Compound 5 is depicted in ball and stick representation with orange carbon atoms. Protein is shown with a green backbone cartoon and specific residues are displayed in stick representation with either green or cyan (M414) carbon atoms. Hydrogen-bonds are denoted as black dotted lines. The surface of the binding site in the vicinity of C6 of the 7-azabenzofuran is shown in light gray. The omitted Fo–Fc electron density is contoured at 2 rmsd in magenta mesh. Image generated with the PyMOL molecular graphics system (v. 1.8, Schrödinger, LLC).