ORGN 491 |
| The cysteine protease, caspase-3 is a critical mediator of apoptotic cell death. Many reports, have demonstrated that these inhibitors could play an important role in the treatment of disorders involving apoptosis such as ischemic injury, burns, endotoximia, sepsis and neonatal hypoxia. Previous efforts identified tetrapeptide ketones/aldehydes as potent and selective inhibitors of caspase-3. However, poor cell permeability precluded their development. Therefore, we have undertaken an iterative discovery process using combinatorial chemistry, parallel synthesis, molecular modelling and structural biology to identify potent and selective dipeptide caspase-3 inhibitors form the tetrapeptide lead. Further optimization led us to the observation that the P4 could be replaced by an oxadiazole phenylacetamide moiety. These inhibitors display potent anti apoptotic activities in a number of cell based systems.
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Technical Achievements in Organic Chemistry Awards
9:30 AM-12:00 PM, Wednesday, 31 August 2005 Washington DC Convention Center -- Ballroom C, Oral
Division of Organic Chemistry |
