Browsing by Author "Pajouhesh, Hossein"

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    Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
    (Elsevier Ltd., 2010-02-15) Pajouhesh, Hassan; Ding, Yanbing; Zhang, Lingyun; Pajouhesh, Hossein; Belardetti, Francesco; Simonson, Eric; Porreca, Frank; Mitscher, Lester A; Snutch, Terrance P; Feng, Zhong Ping; Morrison, Jerrie Lynn; Tringham, Elizabeth W.; Vanderah, Todd W.; Zamponi, Gerald W.
    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 IC(50) 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.
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    Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors
    (Elsevier, 2012-04-19) Pajouhesh, Hassan; Feng, Zhong-Ping; Zhang, Lingyun; Pajouhesh, Hossein; Jiang, Xinpo; Dong, Haiheng; Ding, Yanbing; Porreca, Frank; Belardetti, Francesco; Hendricson, Adam W.; Tringham, Elizabeth W.; Vanderah, Todd W.; Zamponi, Gerald W.; Mitscher, Lester A.; Snutch, Terrance Preston
    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.