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Scaffold-based design and synthesis of potent N-type calcium channel blockers |
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| Authors: | Gerald W. Zamponi Zhong-Ping Feng Lingyun Zhang Hossein Pajouhesh Yanbing Ding Francesco Belardetti Hassan Pajouhesh David Dolphin Lester A. Mitscher Terrance P. Snutch |
| Affiliation: | aDepartment of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada;bNeuromed Pharmaceuticals Ltd, 301-2389 Health Sciences Mall, Vancouver, BC, Canada;cDepartment of Chemistry, University of British Columbia, Vancouver, BC, Canada;dDepartment of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA;eMichael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada |
| Abstract: | The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel. |
| Keywords: | Calcium channel blocker N-type Pain Diphenylmethylpiperazine |
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