%0 journal article
%@ 0968-0896
%A Jones, M.A., Abell, A.D., Morton, J.D., Coxon, J.M., McNabb, S.B., Lee, H.Y.-Y., Aitken, S.G., Mehrtens, J.M., Robertson, L.J.G., Neffe, A.T., Gately, K., Wood, J.M.

%D 2008
%J Bioorganic & Medicinal Chemistry
%N 14
%P 6911-6923 
%R doi:10.1016/j.bmc.2008.05.048
%T Synthesis, biological evaluation and molecular modeling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors
%U https://doi.org/10.1016/j.bmc.2008.05.048
14 
%X 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.