| Autor: |
Narjes F; Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Pomezia, Italy. Frank.Narjes@astrazeneca.com, Crescenzi B, Ferrara M, Habermann J, Colarusso S, Ferreira Mdel R, Stansfield I, Mackay AC, Conte I, Ercolani C, Zaramella S, Palumbi MC, Meuleman P, Leroux-Roels G, Giuliano C, Fiore F, Di Marco S, Baiocco P, Koch U, Migliaccio G, Altamura S, Laufer R, De Francesco R, Rowley M |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2011 Jan 13; Vol. 54 (1), pp. 289-301. Date of Electronic Publication: 2010 Dec 08. |
| DOI: |
10.1021/jm1013105 |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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