title: Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles.
abstract: The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. vassilo@amgen.com
authors.forename: Vassil I
authors.initials: VI
authors.lastname: Ognyanov
authors.forename: Chenera
authors.initials: C
authors.lastname: Balan
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Bo
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gore
authors.forename: Lana
authors.initials: L
authors.lastname: Klionsky
authors.forename: Vu V
authors.initials: VV
authors.lastname: Ma
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Qian
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Xi
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.forename: Dawn
authors.initials: D
authors.lastname: Zhu
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D010147:Pain Measurement; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: C512086:1-(5-chloro-6-(3-methyl-4-(6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo(d)imidazol-2-yl)piperazin-1-yl)pyridin-3-yl)ethane-1,2-diol; D000700:Analgesics; D001562:Benzimidazoles; D010879:Piperazines; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005620:Freund's Adjuvant; D002211:Capsaicin; D002118:Calcium