Frank Narjes,
Benedetta Crescenzi,
Marco Ferrara, J€ Org Habermann,
Stefania Colarusso,
Maria Del,
Rosario Rico Ferreira,
Ian Stansfield,
Angela Claire Mackay,
Immacolata Conte, [......],
Uwe Koch,
Giovanni Migliaccio,
Sergio Altamura,
Ralph Laufer,
Raffaele De,
Michael Rowley,
Istituto Di,
Ricerche Di,
Biologia Molecolare,
P Angeletti Spa
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ABSTRACT: 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), 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.
Journal of Medicinal Chemistry 01/2011; 54:289-301. · 5.25 Impact Factor
