The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile-Part 1
| Autor: | Kathy F. K. Cheung, Jean-Yves Chiva, Satish Dayal, Darren Stead, Carly L. Nichols, Rob Webster, Lee R. Roberts, David Stonehouse, Felice Daverio, Iain Gardner, Andrew Pike, Michael Paradowski, David C. Blakemore, Gilles H. Goetz, Lesa Watson, Chris Pickford, Jared B.J. Milbank, Ye Che, Robert Wybrow, Florian Wakenhut, Keith Statham, Caroline Smith-Burchnell, Samuel Crook, Fiona M. Adam, David C. Pryde, David Leese, Mike Westby, Duncan Hay, Stephen M. Shaw, Tram T. Tran |
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| Rok vydání: | 2014 |
| Předmět: |
Daclatasvir
Hepatitis C virus Hepacivirus Drug Evaluation Preclinical Drug resistance Viral Nonstructural Proteins Pharmacology medicine.disease_cause Antiviral Agents Biochemistry Virus Cell Line Structure-Activity Relationship Dogs Quinoxalines Drug Resistance Viral Drug Discovery medicine Animals Humans Structure–activity relationship Potency Protease Inhibitors General Pharmacology Toxicology and Pharmaceutics NS5A biology Organic Chemistry Valine biology.organism_classification Virology Rats Microsomes Liver Molecular Medicine Half-Life medicine.drug |
| Zdroj: | ChemMedChem. 9:1378-1386 |
| ISSN: | 1860-7179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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