Structure–activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels

Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure–activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.

Graphical abstractThe structure–activity relationship studies of 1,4-dihydropyridine-3-carboxylic acid derived N-type calcium channel blockers were reported. As a consequence of this study, we found orally active 4-(3-chloro-phenyl)-2-methyl-6-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(3,3-diphenylpropyl) ester (21b).Figure optionsDownload full-size imageDownload as PowerPoint slide