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https://hdl.handle.net/2440/53734
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Type: | Journal article |
Title: | Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors |
Author: | Jones, M. Morton, J. Coxon, J. McNabb, S. Lee, H. Aitken, S. Mehrtens, J. Robertson, L. Neffe, A. Miyamoto, S. Bickerstaffe, R. Gately, K. Wood, J. Abell, A. |
Citation: | Bioorganic and Medicinal Chemistry, 2008; 16(14):6911-6923 |
Publisher: | Pergamon-Elsevier Science Ltd |
Issue Date: | 2008 |
ISSN: | 0968-0896 1464-3391 |
Statement of Responsibility: | Matthew A. Jones, James D. Morton, James M. Coxon, Stephen B. McNabb, Hannah Y.-Y. Lee, Steven G. Aitken, Janna M. Mehrtens, Lucinda J.G. Robertson, Axel T. Neffe, Shigeru Miyamoto, Roy Bickerstaffe, Karl Gately, Jacqueline M. Wood and Andrew D. Abell |
Abstract: | A series of N-heterocyclic dipeptide aldehydes 4–13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC50 values of 290 and 25 nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4–13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification. |
Keywords: | Animals Sheep Humans Aldehydes Glycoproteins Dipeptides Binding Sites Structure-Activity Relationship Models, Molecular |
DOI: | 10.1016/j.bmc.2008.05.048 |
Published version: | http://dx.doi.org/10.1016/j.bmc.2008.05.048 |
Appears in Collections: | Aurora harvest 5 Chemistry publications |
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