Caspase inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death, or apoptosis. Publications detailing programs in the pharmaceutical industry have been more frequent in recent years, ranging from SAR studies to clinically relevant animal models of disease. A summary of the work published in this exciting new area is presented, outlining the broad applicability of this fundamental cellular mechanism across several disease indications. This area of research has matured to the level of advancing compounds into clinical trials: VX-740 (Pralnacasan) and VX-765 as anti-inflammatory agents, and IDN-6556, a pan-caspase inhibitor as an anti-apoptotic agent.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

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