Synthesis and biological evaluation of novel piperidine carboxamide derived calpain inhibitors

Calpain inhibitors which are derived from piperidine carboxamides in the P-2 legion were prepared and evaluated for mu-calpain inhibition. In particular, the keto amides 11f and 11j have K-i 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. (C) 2000 Elsevier Science Ltd. All rights reserved.