Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers

To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 4-piperidinecarboxylate and 4-piperidinecyanide derivatives were prepared and evaluated for in vitro and in vivo activity against α1G calcium channel. Among them, several compounds showed good T-type calcium channel inhibitory activity and minimal off-target activity over hERG channel (% inhibition at 10 μM = 61.85–71.99, hERG channel IC50 = 1.57 ± 0.14–4.98 ± 0.36 μM). Selected compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory effect on mechanical allodynia.

Graphical abstractA series of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives (3) based on pharmacophore mapping study were prepared and evaluated for T-type calcium channel (α1G) by patch clamp method. Among them, compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory activity on mechanical allodynia.Figure optionsDownload full-size imageDownload as PowerPoint slide