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.

A 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 as PowerPoint slide