title: Synthesis and calpain inhibitory activity of peptidomimetic compounds with constrained amino acids at the P2 position.
abstract: The effect of incorporating alpha,alpha'-diethylglycine and alpha-aminocyclopentane carboxylic acid at the P(2) position of inhibitors on mu-calpain inhibition was studied. Compound 3 with alpha,alpha'-diethylglycine was over 20-fold more potent than 2 with alpha-aminocyclopentane carboxylic acid. Additionally, 3 was over 35-fold selective for mu-calpain compared to cathepsin B, while 2 was 3-fold selective for cathepsin B compared to mu-calpain. Thus, the conformation induced by the P(2) residue influenced the activities of the compounds versus the closely related cysteine proteases, and suggests an approach to the discovery of selective mu-calpain inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
authors.forename: Rajani
authors.initials: R
authors.lastname: Korukonda
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine
chemical_list: D000596:Amino Acids; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D002154:Calpain; C449002:mu-calpain; D002401:Cathepsin B