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

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 site...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00541