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Bioorg Med Chem Lett. 2008 Sep 1;18(17):4806-8. doi: 10.1016/j.bmcl.2008.07.094. Epub 2008 Jul 27.

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

Author information

1
Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.

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.

PMID:
18694642
PMCID:
PMC2575414
DOI:
10.1016/j.bmcl.2008.07.094
[Indexed for MEDLINE]
Free PMC Article

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