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
| Autor: | Paola Baiocco, Angela C. Mackay, Jörg Habermann, Frank Narjes, Raffaele De Francesco, Caterina Ercolani, Giovanni Migliaccio, Stefania Di Marco, Geert Leroux-Roels, Philip Meuleman, Ralph Laufer, Simone Zaramella, Stefania Colarusso, Immacolata Conte, Fabrizio Fiore, Michael Rowley, Sergio Altamura, Maria del Rosario Rico Ferreira, Benedetta Crescenzi, Uwe Koch, Ian Stansfield, Claudio Giuliano, Maria-Cecilia Palumbi, Marco Ferrara |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 54:289-301 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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