Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1

Tran, Thien Duc, Wakenhut, Florian, Pickford, Chris, Shaw, Stephen, Westby, Mike, Smith-Burchnell, Caroline, Watson, Lesa, Paradowski, Michael, Milbank, Jared, Brimage, Rebecca A., Halstead, Rebecca, Glen, Rebecca, Wilson, Craig P., Adam, Fiona, Hay, Duncan, Chiva, Jean-Yves, Nichols, Carly, Blakemore, David C., Gardner, Iain, Dayal, Satish, Pike, Andrew, Webster, Rob and Pryde, David C. 2014. The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1. ChemMedChem 9 (7) , pp. 1378-1386. 10.1002/cmdc.201400045

Full text not available from this repository.

Abstract

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Wiley
ISSN: 1860-7179
Last Modified: 25 Feb 2019 14:03
URI: http://orca-mwe.cf.ac.uk/id/eprint/112612

Citation Data

Cited 16 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item