MEDI 460 |
| Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million, people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the genotype 1 and relapse patients is moderate at best, with only about 40% of the patients showing sustained virological response. Significant efforts are now directed towards development of therapies that target key enzymes vital to HCV replication and maturation. Macrocyclization strategy has been widely used to depetidize various peptidic inhibitors. X-ray structure of NS3 enzyme reveal a very shallow binding pocket at the catalytic site which makes development of inhibitors a daunting task. In this oral presentation we discuss, the design and the SAR of P1-P3 derived macrocyclic inhibitors that contain a ketoamide trap. Structure activity of the P1-P3 linker as well as the P3 capping region is extensively discussed. Compounds with excellent enzyme binding and cellular activities were identified. X-ray structure of inhibitor bound to the active site of the enzyme is also discussed. Macrocyclization proved to be an effective tool for depeptidization of these inhibitors, imparting enhanced metabolic stability and improved pharmacokinetic properties in the resultant molecules.
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General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |
