2. Academic Validation
  3. 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

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

  • J Med Chem. 2011 Jan 13;54(1):289-301. doi: 10.1021/jm1013105.
Frank Narjes 1,  Benedetta Crescenzi,  Marco Ferrara,  Jörg 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
Affiliations

Affiliation

  • 1 Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Pomezia, Italy. Frank.Narjes@astrazeneca.com
PMID: 21141896 DOI: 10.1021/jm1013105
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111204
    HCV NS5B聚合酶抑制剂
    HCV
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