Synthesis, biological evaluation and molecular modelling of N

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• 作者：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
• 关键词：Calpain ; Isoform selectivity ; Ovine calpain 1 and 2 ; In silico calpain homology model ; Substituted heterocyclic dipeptides ; CAT0059
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 July 2008
• 年：2008
• 卷：16
• 期：14
• 页码：6911-6923
• 全文大小：1074 K

文摘

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.