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.
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 / F. Narjes, B. Crescenzi, M. Ferrara, J. Habermann, S. Colarusso, M. Del Rosario Rico Ferreira, I. Stansfield, A.C. Mackay, I. Conte, C. Ercolani, S. Zaramella, M. Palumbi, P. Meuleman, G. Leroux-Roels, C. Giuliano, F. Fiore, S. Di Marco, P. Baiocco, U. Koch, G. Migliaccio, S. Altamura, R. Laufer, R. De Francesco, M. Rowley. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:1(2011), pp. 289-301.
Titolo: | 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 |
Autori: | |
Parole Chiave: | Dependent RNA-polymerase; chimeric human livers; de-novo initiation; UPA-scid mouse; allosteric inhibitors; nonnucleoside inhibitors; HCVNS5B polymerase; in-vivo; benzimidazole derivates; antiviral activity |
Settore Scientifico Disciplinare: | Settore BIO/10 - Biochimica Settore BIO/13 - Biologia Applicata Settore BIO/14 - Farmacologia |
Data di pubblicazione: | 2011 |
Rivista: | |
Tipologia: | Article (author) |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1021/jm1013105 |
Appare nelle tipologie: | 01 - Articolo su periodico |
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