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 Bioavai

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• 作者：Frank Narjes ; Benedetta Crescenzi ; Marco Ferrara ; J枚rg Habermann ; Stefania Colarusso ; Maria del Rosario Rico Ferreira ; Ian Stansfield ; Angela Claire Mackay ; Immacolata Conte ; Caterina Ercolani ; Simone Zaramella ; Maria-Cecilia Palumbi ; Philip Meuleman ; Geert Leroux-Roels ; Claudio Giuliano ; Fabrizio Fiore ; Stefania Di Marco ; Paola Baiocco ; Uwe Koch ; Giovanni Migliaccio ; Sergio Altamura ; Ralph Laufer ; Raffaele De Francesco ; Michael Rowley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：289-301
• 全文大小：1130K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

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鈭抋ctivity 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.