发现新型基于噻吩的丙型肝炎NS5B聚合酶拇指口袋2变构抑制剂，其效力和理化性质得到改善。
Discovery of Novel Thiophene-Based, Thumb Pocket 2 Allosteric Inhibitors of the Hepatitis C NS5B Polymerase with Improved Potency and Physicochemical Profiles.
作者信息
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
机构信息
Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7V 4A7, Canada.
出版信息
J Med Chem. 2016 Jul 14;59(13):6293-302. doi: 10.1021/acs.jmedchem.6b00541. Epub 2016 Jul 1.
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.
丙型肝炎病毒蛋白NS3/4A蛋白酶、NS5B聚合酶和NS5A是直接作用抗病毒疗法经过临床验证的靶点。NS5B聚合酶可通过核苷或核苷酸类似物的作用直接受到抑制，或在多个明确的位点受到变构抑制。在此，我们描述了一系列作用于拇指袋2位点的噻吩羧酸盐NS5B聚合酶变构抑制剂的进一步研发情况。洛米布韦（1）是一种NS5B变构抑制剂，已证明其与其他直接作用抗病毒药物联合使用时具有出色的抗病毒活性和潜在临床应用价值。对该系列进行进一步探索和研发的工作产生了化合物23，该化合物具有相当的效力且理化性质有所改善。
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