Synthesis and structure–activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease

The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of α-Fas-induced liver injury.

P4 derivatives of the oxamyl dipeptide caspase inhibitors are reported. Compounds 29 and 36 exhibited moderate membrane permeability and potent in vivo efficacy in an α-Fas-induced liver injury model.Figure optionsDownload as PowerPoint slide