Design of Potent, Orally Available Antagonists of the Transient Receptor Potential Vanilloid 1.
Structure−Activity Relationships of 2-Piperazin-1-yl-1H-benzimidazoles

Ognyanov, Vassil I.; Balan, Chenera; Bannon, Anthony W.; Bo, Yunxin; Dominguez, Celia; Fotsch, Christopher; Gore, Vijay K.; Klionsky, Lana; Ma, Vu V.; Qian, Yi-Xin; Tamir, Rami; Wang, Xianghong; Xi, Ning; Xu, Shimin; Zhu, Dawn; Gavva, Narender R.; J. S. Treanor, James; Norman, Mark H.

doi:10.1021/jm060065y.s001

jm060065y_si_001.pdf (116.86 kB)

Design of Potent, Orally Available Antagonists of the Transient Receptor Potential Vanilloid 1. Structure−Activity Relationships of 2-Piperazin-1-yl-1H-benzimidazoles

journal contribution

posted on 2006-06-15, 00:00 authored by 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

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).