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https://hdl.handle.net/2440/53734
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dc.contributor.author | Jones, M. | - |
dc.contributor.author | Morton, J. | - |
dc.contributor.author | Coxon, J. | - |
dc.contributor.author | McNabb, S. | - |
dc.contributor.author | Lee, H. | - |
dc.contributor.author | Aitken, S. | - |
dc.contributor.author | Mehrtens, J. | - |
dc.contributor.author | Robertson, L. | - |
dc.contributor.author | Neffe, A. | - |
dc.contributor.author | Miyamoto, S. | - |
dc.contributor.author | Bickerstaffe, R. | - |
dc.contributor.author | Gately, K. | - |
dc.contributor.author | Wood, J. | - |
dc.contributor.author | Abell, A. | - |
dc.date.issued | 2008 | - |
dc.identifier.citation | Bioorganic and Medicinal Chemistry, 2008; 16(14):6911-6923 | - |
dc.identifier.issn | 0968-0896 | - |
dc.identifier.issn | 1464-3391 | - |
dc.identifier.uri | http://hdl.handle.net/2440/53734 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | 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 | - |
dc.language.iso | en | - |
dc.publisher | Pergamon-Elsevier Science Ltd | - |
dc.source.uri | http://dx.doi.org/10.1016/j.bmc.2008.05.048 | - |
dc.subject | Animals | - |
dc.subject | Sheep | - |
dc.subject | Humans | - |
dc.subject | Aldehydes | - |
dc.subject | Glycoproteins | - |
dc.subject | Dipeptides | - |
dc.subject | Binding Sites | - |
dc.subject | Structure-Activity Relationship | - |
dc.subject | Models, Molecular | - |
dc.title | Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1016/j.bmc.2008.05.048 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Abell, A. [0000-0002-0604-2629] | - |
Appears in Collections: | Aurora harvest 5 Chemistry publications |
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