Synthesis and calpain inhibitory activity of peptidomimetic compounds with constrained amino acids at the P2 position

The effect of incorporating α,α′-diethylglycine and α-aminocyclopentane carboxylic acid at the P₂ position of inhibitors on μ-calpain inhibition was studied. Compound 3 with α,α′-diethylglycine was over 20-fold more potent than 2 with α-aminocyclopentane carboxylic acid. Additionally, 3 was over 35-fold selective for μ-calpain compared to cathepsin B, while 2 was 3-fold selective for cathepsin B compared to μ-calpain. Thus, the conformation induced by the P₂ residue influenced the activities of the compounds versus the closely related cysteine proteases, and suggests an approach to the discovery of selective μ-calpain inhibitors.