Novel T-type calcium channel blockers and 3-D pharmacophore based virtual screening

초록

A small molecule library of piperazinylalkyl isoxazole and oxazole derivatives was designed, synthesized and evaluated for blocking effects on T-type Ca2+ channel. Several ligands were identified to possess high inhibitory activity for the T-type Ca2+ channel. The compound KKHB1206103 showed in vivo efficacy in the neuropathic pain model and formalin test. A three-dimensional pharmacophore model was developed for T-type calcium channel blockers in order to map common structural features of highly active compounds by using CATALYST program. Virtual screening of the commercial databases was done by using a three dimensional pharmacophore model developed for T-type calcium channel blockers. Biological evaluation of 25 selected virtual hits resulted in the discovery of a highly potent compound K284-3446 with IC50 value of 0.10M, eight times as potent as the known selective T-type calcium channel blocker, mibefradil. Search for similar compounds in the Ion channel database gave a number of potent and selective T-type calcium channel blockers. SAR of these compounds was understood by developing a new pharmacophore by using selected highly active compounds.