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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.

Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.

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.

Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.

Parallel synthesis was used to explore the SAR of a peptidomimetic caspase inhibitor. The most potent compound had nanomolar activity against caspases 1, 3, 6, 7, and 8.

A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.

A systematic study of interleukin-1 beta converting enzyme (ICE, caspase-1) and caspase-3 (CPP32, apopain) inhibitors incorporating a P2-P3 conformationally constrained dipeptide mimetic is reported. Depending on the nature of the P4 substituent, highly selective inhibitors of both Csp-1 or Csp-3 were obtained.