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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 14; pp. 4132 - 4140
• Main Authors: Beaulieu, Pierre L., Coulombe, René, Duan, Jianmin, Fazal, Gulrez, Godbout, Cédrickx, Hucke, Oliver, Jakalian, Araz, Joly, Marc-André, Lepage, Olivier, Llinàs-Brunet, Montse, Naud, Julie, Poirier, Martin, Rioux, Nathalie, Thavonekham, Bounkham, Kukolj, George, Stammers, Timothy A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.07.2013; Elsevier
• Subjects: Allosteric inhibition; Allosteric properties; Allosteric Regulation; Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Half-Life; HCV NS5B polymerase; Hepacivirus - enzymology; Hepacivirus - physiology; Hepatitis C virus; Life Sciences & Biomedicine; Molecular Docking Simulation; Non-nucleoside inhibitor; ortho-Aminobenzoates - chemistry; Pharmacology & Pharmacy; Physical Sciences; Protein Structure, Tertiary; Quinazolinones - chemical synthesis; Quinazolinones - chemistry; Quinazolinones - pharmacokinetics; Rats; Science & Technology; Structure-Activity Relationship; Structure-based drug design; Thumb pocket 2; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; Non-nucleoside inhibitor; HCV NS5B polymerase; Allosteric inhibition; Structure-based drug design; Thumb pocket 2; PRECLINICAL CHARACTERIZATION; BI 207127; POLYMERASE; RIBAVIRIN; COMBINATION; PROTEASE INHIBITOR; NONNUCLEOSIDE INHIBITOR; DIRECT-ACTING ANTIVIRALS; INTERFERON-FREE REGIMEN; TREATMENT-NAIVE PATIENTS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.05.037

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.