Synthesis and biological evaluation of novel piperidine carboxamide derived calpain inhibitors

Calpain inhibitors which are derived from piperidine carboxamides in the P2 region were prepared and evaluated for μ-calpain inhibition. In particular, the keto amides 11f and 11j have Ki of 30 and 9 nM and display a more than 100-fold selectivity over the closely related cysteine protease cathepsin B. Furthermore, these compounds inhibit NMDA induced convulsions in mice indicating that calpain inhibition in brain results in some anticonvulsive properties.