Scaffold-based design and synthesis of potent N-type calcium channel blockers

  • Bioorg Med Chem Lett. 2009 Nov 15;19(22):6467-72. doi: 10.1016/j.bmcl.2009.09.008.
Gerald W Zamponi  1 ,  Zhong-Ping Feng ,  Lingyun Zhang ,  Hossein Pajouhesh ,  Yanbing Ding ,  Francesco Belardetti ,  Hassan Pajouhesh ,  David Dolphin ,  Lester A Mitscher ,  Terrance P Snutch
Affiliations
  • 1. Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
PMID: 19815411 DOI: 10.1016/j.bmcl.2009.09.008
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.

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