Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier

Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC50 asymptotic to 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability. The analogs obtained exhibited improved potency against HCV genotypes 1a, 1b, 3a and 4a compared to the clinically approved candidate daclatasvir with EC50 values in the low picomolar range and SI(50)s > 7 orders of magnitude. Compound 15, a symmetrically m-, m' -substituted diphenyl ethyne analog, was 150-fold more potent than daclatasvir against GT 3a, while compound 33, an asymmetrically m-, p-substituted diphenyl ethyne analog, was 35-fold more potent than daclatasvir against GT 3a. In addition, compound 15 exhibited a higher resistance barrier than daclatasvir against genotype 1b. (c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The discovery of potent NS5A inhibitors against HCV genotype 1b, with improved activity against other genotypes and good metabolic stability, is reported. The variations in cap conformation and compound symmetry were studied and found to have an impact on both potency and metabolic stability. The analogs obtained showed higher potency compared to the clinically approved candidate daclatasvir across multiple genotypes.