Structure–activity relationships of diphenylpiperazine N-type calcium channel inhibitors

A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC50 values in the range of 10–150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.

The synthesis and discovery of the potent N-type calcium channel blocker 5 (IC50 = 0.05 μM) and 21 (IC50 = 0.15 μM) is described. Following oral administration compounds 5 and 21 exhibit analgesic efficacy in the spinal nerve ligation model of neuropathic pain.Figure optionsDownload as PowerPoint slide