Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions

Abstract

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.

Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors

“…The NS5A protein has no identified enzymatic activity or known homologue in eukaryotes or prokaryotes, making the mechanism of action for the inhibitors unclear [ 24 , 25 ]. Moreover, until today, there is no available crystal structure of the protein complexed with any known inhibitor, making it difficult to use structure-based drug design approaches [ 26 ]. Therefore, based on the fact that NS5A inhibitors are most commonly symmetric peptidomimetics consisting of peptide-based caps connected to a linker (core), an attempt to improve drug positioning in the binding pocket and strengthen interaction forces was carried out by changing both the core and caps to possibly improve potency across genotypes and resistance profiles.…”

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

“…A series of aminal-linked tetracyclic inhibitors of the HCV NS5A replication complex derived from the benzofuran prototype MK-4882 ( 388 ) has been developed in which a poorly basic indole nitrogen atom is part of the geminal diheteroatomic motif, as exemplified by 390 (Figure ). In order to improve the antiviral activities of 388 toward clinically relevant HCV GTs and resistance mutations, the benzofuran core was converted to an indole scaffold. This molecular edit allowed the introduction of a bridge between the indole nitrogen atom and C5 carbon of the proximal phenyl ring through either an ethylene ( 389 ) or an oxygen-containing linker ( 390 ) that enabled substitution in a region of the pharmacophore known to be tolerant.…”

Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via highthroughput virtual screening and in vitro evaluations

“…In May 2011, the United States Food and Drug Administration (U.S. FDA) approved the first generation of direct-acting antivirals (DAAs), Boceprevir (Chen & Njoroge, 2010) and Telaprevir (Kwong et al, 2011), to treat HCV. Since then, numerous highly potent DAAs targeting the NS3/4A protease (Rosenquist et al, 2014;Ng et al, 2018), NS5A (Belema et al, 2014;Yu et al, 2018) and NS5B polymerase (Sofia, 2016;ElKassas et al, 2017) have been developed. Yet, some are only effective against certain genotypes.…”