Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors

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 (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.

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

“…5) bound to I-II [164]. Similar conformations have been reported for docked structures (see later for a discussion) [175,176]. The observation that calpain (and other proteases) recognize and bind a -strand conformation in the backbone of inhibitors led to conformationally a Ac (acetyl); Dab (L-2,3-diaminobutyryl); Orn (ornithine).…”

“…Significantly, the corresponding primary alcohol precursor of (9b) is also a potent and calpain 2-selective inhibitor (IC 50 = 700 nM). Inhibitors (8a) (CAT0059) and (9b) (CAT811) have been reported to protect sheep lenses from calcium-induced opacification in an in vitro model for cataract formation [176,178,179,234].…”

Structure-Based Virtual Screening and Biological Evaluation of a Calpain Inhibitor for Prevention of Selenite-Induced Cataractogenesis in an in Vitro System

“…These results suggest that the addition of HTS08688 to the DMEM medium containing selenite, partially prevented the occurrence of lenticular opacification caused by exposure to selenite, possibly by inhibiting the calpain protein. The results of the current investigation corroborate those of an earlier study by Jones et al, 63 wherein the selective calpain inhibitor, CAT0059, protected the lens from opacification in an in vitro ovine lens culture system. Quantitative Analysis of Biochemical Parameters.…”

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…Compound Name* Reference calpastatin and it synthetic derivatives Calpastatin, CP1B, PCP1B, 7-mer-PCP1B, 11R-CS, CP1B-[4-23] (Betts et al, 2003;Fiorino et al, 2007;Gil-Parrado et al, 2003;Hanna et al, 2008;Pfizer et al, 2008;Wu et al, 2003) Peptidomimetic calpain inhibitors Inhibitors with modification at the P2 position Compounds 2 to 7 (Donkor and Korukonda, 2008;Donkor et al, 2000;Sanders and Donkor, 2006) Inhibitors with modification at the P3 position Compounds 8 to 10 (Jones et al, 2008) Inhibitors with modification in the P1 -P3 region…”