Open AccessDiscovery of Quinoxaline-Based P1–P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants
Author(s) -
Desaboini Nageswara Rao,
J. Zephyr,
M. Henes,
Elise T Chan,
Ashley N. Matthew,
Adam K. Hedger,
Hasahn L Conway,
Mohsan Saeed,
Alicia Newton,
Christos J. Petropoulos,
Wei Huang,
Neşe Kurt Yilmaz,
Celia A. Schiffer,
Akbar Ali
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00554
Subject(s) - quinoxaline , chemistry , genotype , hepatitis c virus , ns3 , stereochemistry , protease , drug resistance , structure–activity relationship , lead compound , virology , protease inhibitor (pharmacology) , virus , combinatorial chemistry , pharmacology , biochemistry , enzyme , biology , microbiology and biotechnology , organic chemistry , in vitro , gene , antiretroviral therapy , viral load
The three pan-genotypic HCV NS3/4A protease inhibitors (PIs) currently in clinical use-grazoprevir, glecaprevir, and voxilaprevir-are quinoxaline-based P2-P4 macrocycles and thus exhibit similar resistance profiles. Using our quinoxaline-based P1-P3 macrocyclic lead compounds as an alternative chemical scaffold, we explored structure-activity relationships (SARs) at the P2 and P4 positions to develop pan-genotypic PIs that avoid drug resistance. A structure-guided strategy was used to design and synthesize two series of compounds with different P2 quinoxalines in combination with diverse P4 groups of varying sizes and shapes, with and without fluorine substitutions. Our SAR data and cocrystal structures revealed the interplay between the P2 and P4 groups, which influenced inhibitor binding and the overall resistance profile. Optimizing inhibitor interactions in the S4 pocket led to PIs with excellent antiviral activity against clinically relevant PI-resistant HCV variants and genotype 3, providing potential pan-genotypic inhibitors with improved resistance profiles.