Structure–activity study of l-amino acid-based N-type calcium channel blockers

Abstract

Synthesis and structure–activity relationship (SAR) study of l-amino acid-based N-type calcium channel blockers are described. The compounds synthesized were evaluated for inhibitory activity against both N-type and L-type calcium channels focusing on selectivity to reduce cardiovascular side effects due to blocking of L-type calcium channels. In the course of screening of our compound library, N-( t-butoxycarbonyl)- l-aspartic acid derivative 1a was identified as an initial lead compound for a new series of N-type calcium channel blockers, which inhibited calcium influx into IMR-32 human neuroblastoma cells with an IC 50 of 3.4 μM. Compound 1a also exhibited blockade of N-type calcium channel current in electrophysiological experiment using IMR-32 cells (34% inhibition at 10 μM, n=3). As a consequence of conversion of amino acid residue of 1a, compound 12a, that include N-( t-butoxycarbonyl)- l-cysteine, was found to be a potent N-type calcium channel blocker with an IC 50 of 0.61 μM. Thus, l-cysteine was selected as a potential structural motif for further modification. Optimization of C- and N-terminals of l-cysteine using S-cyclohexylmethyl- l-cysteine as a central scaffold led to potent and selective N-type calcium channel blocker 21f, which showed improved inhibitory potency (IC 50 0.12 μM) and 12-fold selectivity for N-type calcium channels over L-type channels.