Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/53734
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dc.contributor.authorJones, M.-
dc.contributor.authorMorton, J.-
dc.contributor.authorCoxon, J.-
dc.contributor.authorMcNabb, S.-
dc.contributor.authorLee, H.-
dc.contributor.authorAitken, S.-
dc.contributor.authorMehrtens, J.-
dc.contributor.authorRobertson, L.-
dc.contributor.authorNeffe, A.-
dc.contributor.authorMiyamoto, S.-
dc.contributor.authorBickerstaffe, R.-
dc.contributor.authorGately, K.-
dc.contributor.authorWood, J.-
dc.contributor.authorAbell, A.-
dc.date.issued2008-
dc.identifier.citationBioorganic and Medicinal Chemistry, 2008; 16(14):6911-6923-
dc.identifier.issn0968-0896-
dc.identifier.issn1464-3391-
dc.identifier.urihttp://hdl.handle.net/2440/53734-
dc.description.abstractA 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.statementofresponsibilityMatthew 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.isoen-
dc.publisherPergamon-Elsevier Science Ltd-
dc.source.urihttp://dx.doi.org/10.1016/j.bmc.2008.05.048-
dc.subjectAnimals-
dc.subjectSheep-
dc.subjectHumans-
dc.subjectAldehydes-
dc.subjectGlycoproteins-
dc.subjectDipeptides-
dc.subjectBinding Sites-
dc.subjectStructure-Activity Relationship-
dc.subjectModels, Molecular-
dc.titleSynthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors-
dc.typeJournal article-
dc.identifier.doi10.1016/j.bmc.2008.05.048-
pubs.publication-statusPublished-
dc.identifier.orcidAbell, A. [0000-0002-0604-2629]-
Appears in Collections:Aurora harvest 5
Chemistry publications

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