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	Vassil I Ognyanov, Chenera Balan, Anthony W Bannon, Yunxin Bo, Celia Dominguez, Christopher Fotsch, Vijay K Gore, Lana Klionsky, Vu V Ma, Yi-Xin Qian, Rami Tamir, Xianghong Wang, Ning Xi, Shimin Xu, Dawn Zhu, Narender R Gavva, James J S Treanor, Mark H Norman
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 12 Pg. 3719-42 (Jun 15 2006) ISSN: 0022-2623 [Print] United States
PMID	16759115 (Publication Type: Journal Article)
Chemical References	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 Analgesics Benzimidazoles Piperazines Recombinant Proteins TRPV Cation Channels Trpv1 protein, rat Freund's Adjuvant Capsaicin Calcium
Topics	Administration, Oral Analgesics (chemical synthesis, chemistry, pharmacology) Animals Benzimidazoles (chemical synthesis, chemistry, pharmacology) Biological Availability CHO Cells Calcium (metabolism) Capsaicin (pharmacology) Cricetinae Cricetulus Freund's Adjuvant Hot Temperature Hydrogen-Ion Concentration Hyperalgesia (chemically induced, drug therapy) Male Pain Measurement Piperazines (chemical synthesis, chemistry, pharmacology) Rats Rats, Sprague-Dawley Recombinant Proteins (antagonists & inhibitors) Stereoisomerism Structure-Activity Relationship TRPV Cation Channels (antagonists & inhibitors)

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