Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

作者：Narjes Frank^*; Crescenzi Benedetta; Ferrara Marco; Habermann Jorg; Colarusso Stefania; Ferreira Maria del Rosario Rico; Stansfield Ian; Mackay Angela Claire; Conte Immacolata; Ercolani Caterina; Zaramella Simone; Palumbi Maria Cecilia; Meuleman Philip; Leroux Roels Geert; Giuliano Claudio; Fiore Fabrizio; Di Marco Stefania; Baiocco Paola; Koch Uwe; Migliaccio Giovanni; Altamura Sergio; Laufer Ralph; De Francesco Raffaele; Rowley Michael

来源：Journal of Medicinal Chemistry, 2011, 54(1): 289-301.

DOI：10.1021/jm1013105

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain Structure activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection

• 出版日期2011-1-13