Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups
| Autor: | Srikanth Venkatraman, Wanli Wu, Melissa Blackman, F. George Njoroge, Vincent Madison, Francisco Velazquez |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Proline
Clinical Biochemistry Pharmaceutical Science Hepacivirus Viral Nonstructural Proteins Antiviral Agents Biochemistry Virus Telaprevir Serine Structure-Activity Relationship chemistry.chemical_compound Boceprevir Drug Discovery medicine Humans Protease Inhibitors Molecular Biology chemistry.chemical_classification Organic Chemistry Hepatitis C medicine.disease Amides Amino acid Enzyme chemistry Hepatocellular carcinoma Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 20:2151-2155 |
| ISSN: | 0960-894X |
| Popis: | Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P(1) had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P(1) group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir. |
| Databáze: | OpenAIRE |
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