Scaffold-based design and synthesis of potent N-type calcium channel blockers
Zamponi, Gerald W.; Feng, Zhong-Ping; Zhang, Lingyun; Pajouhesh, Hossein; Ding, Yanbing; Belardetti, Francesco; Pajouhesh, Hassan; Dolphin, David; Mitscher, Lester A.; Snutch, Terrance P
Bioorganic & Medicinal Chemistry Letters
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 (I) and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon i.p. 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.