Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Pajouhesh, Hassan²  Feng, Zhong-Ping^2,3  Zhang, Lingyun²  Pajouhesh, Hossein²  Jiang, Xinpo²  Hendricson, Adam²  Dong, Haiheng²  Tringham, Elizabeth²  Ding, Yanbing²  Vanderah, Todd W.⁴  Porreca, Frank⁴  Belardetti, Francesco²  Zamponi, Gerald W.³  Mitscher, Lester A.⁵  Snutch, Terrance P.¹ 

[1] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada

[2] Zalicus Pharmaceut Ltd, Vancouver, BC, Canada

[3] Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB, Canada

[4] Univ Arizona, Dept Pharmacol, Tucson, AZ USA

[5] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

关键词: N-Type calcium channel;    Trimethoxybenzyl piperazine;    Pain;    hERG potassium channel;    L-Type calcium channel;   

DOI  :  10.1016/j.bmcl.2012.04.054

来源: Elsevier

【 摘 要 】

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 (similar to 120-fold) and L-type (similar to 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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