Synthesis and calpain inhibitory activity of peptidomimetic compounds with constrained amino acids at the P2 position
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-aminoc...
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Published in | Bioorganic & medicinal chemistry letters Vol. 18; no. 17; pp. 4806 - 4808 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
01.09.2008
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2008.07.094 |