2. Academic Validation
  3. Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype

Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype

  • Bioorg Med Chem Lett. 2013 Jul 15;23(14):4132-40. doi: 10.1016/j.bmcl.2013.05.037.
Pierre L Beaulieu 1,  René Coulombe,  Jianmin Duan,  Gulrez Fazal,  Cédrickx Godbout,  Oliver Hucke,  Araz Jakalian,  Marc-André Joly,  Olivier Lepage,  Montse Llinàs-Brunet,  Julie Naud,  Martin Poirier,  Nathalie Rioux,  Bounkham Thavonekham,  George Kukolj,  Timothy A Stammers
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. resgeneral.lav@boehringer-ingelheim.com
PMID: 23768906 DOI: 10.1016/j.bmcl.2013.05.037
Abstract

We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.

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