Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep).

Authors: William H Parsons, Raul R Calvo, Wing Cheung, Yu-Kai Lee, Sharmila Patel, Jian Liu, Mark A Youngman, Scott L Dax, Dennis Stone, Ning Qin, Tasha Hutchinson, Mary Lou Lubin, Sui-Po Zhang, Michael Finley, Yi Liu, Michael R Brandt, Christopher M Flores, Mark R Player

Journal, date & volume: J. Med. Chem., 2015 May 14 , 58, 3859-74

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25850459

Abstract
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.