title: Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors.
abstract: 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.
authors.affiliation: Zalicus Pharmaceuticals Ltd, 301-2389 Health Sciences Mall, Vancouver, BC, Canada.
authors.forename: Hassan
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.forename: Hossein
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: Xinpo
authors.initials: X
authors.lastname: Jiang
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.forename: Haiheng
authors.initials: H
authors.lastname: Dong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tringham
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Ding
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Francesco
authors.initials: F
authors.lastname: Belardetti
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Lester A
authors.initials: LA
authors.lastname: Mitscher
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C534047:1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine; D000700:Analgesics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010879:Piperazines