| 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 |
| Volume | 22 |
| Issue | 12 |
| Pagination | 4153-8 |
| Date Published | 2012 Jun 15 |
| ISSN | 1464-3405 |
| 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 |
| Abstract | 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. |
| DOI | 10.1016/j.bmcl.2012.04.054 |
| Alternate Journal | Bioorg. Med. Chem. Lett. |
| PubMed ID | 22579422 |
| Grant List | / / Canadian Institutes of Health Research / Canada |
Faculty Member Reference:
Frank Porreca, PhD
Todd Vanderah, PhD