MEDI 462 |
| The hepatitis C virus (HCV) infection is the major cause of chronic liver disease. The HCV NS3 serine protease is essential for viral replication. It has been a target of choice for intensive drug discovery research in recent years. We have focused on developing novel moieties as the P3 capping group. It was found that tert-leucinol derived beta-diamino group was one of the best cappings examined. Further SAR on the primary amine led to the discovery of cyclic imide groups. This class of HCV protease inhibitors, represented by structure 1, had excellent enzyme assay potency (Ki* = 4 nM). They were highly selective against Human Neutrophil Elastase (HNE). They were also very potent in cell-based replicon assay (EC50 = 12 nM). Compound 1 had good rat and dog PK profile with moderate bioavailability. The SAR development and pharmacokinetic profiles of these compounds will be discussed.
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General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |
