Lead discovery and optimization of T-type calcium channel blockers

A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with α1G and α1H clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch–clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC50 values than Mibefradil.

Novel series of piperazine derivatives with hypothetical pharmacophoric features were prepared and evaluated for T-type calcium channel (α1G) by FDSS assay and patch clamp method. Among them, alkanamide derivatives with 4-arylsubstituted piperazine (7b, 9j, 11b, 11g, 11h) showed better efficacy than Mibefradil.Figure optionsDownload as PowerPoint slide