Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles
详细信息 查看全文
- 作者：John J. Court ; Carl Poisson ; Andrzej Ardzinski ; Darius Bilimoria ; Laval Chan ; Kishan Chandupatla ; Nathalie Chauret ; Philip N. Collier ; Sanjoy Kumar Das ; Francois Denis ; Warren Dorsch ; Ganesh Iyer ; David Lauffer ; Lucille L’Heureux ; Pan Li ; Brian S. Luisi ; Nagraj Mani ; Suganthi Nanthakumar ; Olivier Nicolas ; B. Govinda Rao ; Steven Ronkin ; Subajini Selliah ; Rebecca S. Shawgo ; Qing Tang ; Nathan D. Waal ; Constantin G. Yannopoulos ; Jeremy Green
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：July 14, 2016
- 年：2016
- 卷：59
- 期：13
- 页码：6293-6302
- 全文大小：447K
- 年卷期：0
- ISSN：1520-4804
文摘
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.