Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles

• Published in: Journal of medicinal chemistry 2016-07, Vol.59 (13), p.6293-6302
• Main Authors: Court, John J, Poisson, Carl, Ardzinski, Andrzej, Bilimoria, Darius, Chan, Laval, Chandupatla, Kishan, Chauret, Nathalie, Collier, Philip N, Das, Sanjoy Kumar, Denis, Francois, Dorsch, Warren, Iyer, Ganesh, Lauffer, David, L’Heureux, Lucille, Li, Pan, Luisi, Brian S, Mani, Nagraj, Nanthakumar, Suganthi, Nicolas, Olivier, Rao, B. Govinda, Ronkin, Steven, Selliah, Subajini, Shawgo, Rebecca S, Tang, Qing, Waal, Nathan D, Yannopoulos, Constantin G, Green, Jeremy
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cyclohexanols - chemistry; Cyclohexanols - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Hepacivirus - drug effects; Hepacivirus - enzymology; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00541

The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.