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

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 17; pp. 4806 - 4808
• Main Authors: Donkor, Isaac O., Korukonda, Rajani
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2008; Elsevier
• Subjects: Amino Acids - chemistry; Animals; Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Calpain; Calpain - antagonists & inhibitors; Cathepsin; Cathepsin B - antagonists & inhibitors; Constrained amino acids; Cysteine proteases; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - pharmacology; Drug Design; Humans; Inhibitors; Medical sciences; Miscellaneous; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Peptidomimetics; Pharmacology. Drug treatments; Swine; Cysteine proteases; Calpain; Cathepsin; Inhibitors; Peptidomimetics; Constrained amino acids; Molecular rigidity; Enzyme; Aminoamide; Cysteine endopeptidases; Peptidomimetic compound; Enzyme inhibitor; Steric hindrance; Selectivity; Aldehyde; Biological activity; Peptidases; Hydrolases; Carboxamide; Calpain;Cathepsin;Cysteine proteases;Peptidomimetics;Constrained amino acids;Inhibitors; Chemical synthesis; Cyclopentane derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.07.094

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