|Title||Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Pajouhesh H, Feng Z-P, Zhang L, Pajouhesh H, Jiang X, Hendricson A, Dong H, Tringham E, Ding Y, Vanderah TW, Porreca F, Belardetti F, Zamponi GW, Mitscher LA, Snutch TP|
|Journal||Bioorg Med Chem Lett|
|Date Published||2012 Jun 15|
|Keywords||Analgesics, Animals, Calcium Channel Blockers, Calcium Channels, L-Type, Calcium Channels, N-Type, Disease Models, Animal, Ether-A-Go-Go Potassium Channels, Hyperalgesia, Neuralgia, Piperazines, Rats, Rats, Sprague-Dawley, Spinal Nerves, Structure-Activity Relationship|
We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.
|Alternate Journal||Bioorg. Med. Chem. Lett.|
|Grant List||/ / Canadian Institutes of Health Research / Canada|
Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors.
Faculty Member Reference:
Frank Porreca, PhD
Todd Vanderah, PhD