Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors.
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 (IC(50) values of 290 and 25nM 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.
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
Matthew A
MA
Jones
James D
JD
Morton
James M
JM
Coxon
Stephen B
SB
McNabb
Hannah Y-Y
HY
Lee
Steven G
SG
Aitken
Janna M
JM
Mehrtens
Lucinda J G
LJ
Robertson
Axel T
AT
Neffe
Shigeru
S
Miyamoto
Roy
R
Bickerstaffe
Karl
K
Gately
Jacqueline M
JM
Wood
Andrew D
AD
Abell
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D012756:Sheep; D013329:Structure-Activity Relationship
D000447:Aldehydes; D004151:Dipeptides; D006023:Glycoproteins; C039304:calpain inhibitors