2. Academic Validation
  3. Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles

Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles

  • J Med Chem. 2006 Jun 15;49(12):3719-42. doi: 10.1021/jm060065y.
Vassil I Ognyanov 1,  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
Affiliations

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. vassilo@amgen.com
PMID: 16759115 DOI: 10.1021/jm060065y
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).

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