Stroke is the number one cause of adult disability and the third leading cause of death in the USA. There remains an urgent need for effective stroke therapies. Caspases are a family of cysteine proteases that play key roles in mediating inflammation and apoptosis (programmed cell death). In Phase I we discovered a class of novel small-molecule caspase inhibitors. The lead compound, Co 105941, is a potent inhibitor of caspase-1 and caspase-3. It has anti-apoptotic activity in vitro and in vivo. Most importantly, intravenous infusion of Co 105941 produced robust neuroprotective effects in a rat model is ischemic stroke. The compound was well tolerated at the dose that produced neuroprotection. In Phase II, we propose to fully characterize the neuroprotective properties of Co 105941 in rat models of focal and global ischemia. In addition, we will synthesize and profile analogues of Co 105941 to further optimize the lead. The overall goal of the program is to identify small molecule caspase inhibitors suitable for clinical development for the treatment of stroke.
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