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

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Abstract

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.

Graphical abstract

Peptidomimetic with P2 α-aminocyclopentane carboxylic acid. μ-Calpain inhibition, Ki = 1.94 μM, cathepsin B inhibition, Ki = 0.88 μM. Peptidomimetic with P2 α,α′-diethylglycine. μ-Calpain inhibition, Ki = 0.08 μM, cathepsin B inhibition, Ki = 2.91 μM.

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Acknowledgment

This work was supported by NIH Grant R15 HL083968-01 to I.O.D.

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