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
  • 1. Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Pomezia, Italy. [email protected]
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111204
    MK3281
    HCV NS5B Polymerase Inhibitor
    target: HCV
    Research Areas: Infection