Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 24; pp. 6879 - 6885
• Main Authors: Stammers, Timothy A., Coulombe, René, Duplessis, Martin, Fazal, Gulrez, Gagnon, Alexandre, Garneau, Michel, Goulet, Sylvie, Jakalian, Araz, LaPlante, Steven, Rancourt, Jean, Thavonekham, Bounkham, Wernic, Dominik, Kukolj, George, Beaulieu, Pierre L.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2013; Elsevier
• Subjects: additive effect; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; cell culture; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Direct-acting antiviral; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCV NS5B polymerase; Hepacivirus - enzymology; Hepatitis C virus; inhibitory concentration 50; Life Sciences & Biomedicine; Molecular Docking Simulation; Non-nucleoside inhibitor; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Protein Structure, Tertiary; replicon; 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; Thumb Pocket 2; Structure-based drug design; Direct-acting antiviral; ALPHA-2A; TELAPREVIR; PEGYLATED-INTERFERON; RIBAVIRIN; COMBINATION; DISCOVERY; THERAPY; ANTIVIRAL ACTIVITY; HEPATITIS-C
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.09.102

Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100nanomolar.