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).
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.
authors: William H
authors: WH
authors: Parsons
authors: Raul R
authors: RR
authors: Calvo
authors: Wing
authors: W
authors: Cheung
authors: Yu-Kai
authors: YK
authors: Lee
authors: Sharmila
authors: S
authors: Patel
authors: Jian
authors: J
authors: Liu
authors: Mark A
authors: MA
authors: Youngman
authors: Scott L
authors: SL
authors: Dax
authors: Dennis
authors: D
authors: Stone
authors: Ning
authors: N
authors: Qin
authors: Tasha
authors: T
authors: Hutchinson
authors: Mary Lou
authors: ML
authors: Lubin
authors: Sui-Po
authors: SP
authors: Zhang
authors: Michael
authors: M
authors: Finley
authors: Yi
authors: Y
authors: Liu
authors: Michael R
authors: MR
authors: Brandt
authors: Christopher M
authors: CM
authors: Flores
authors: Mark R
authors: MR
authors: Player
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002351:Carrageenan; D004285:Dogs; D005620:Freund's Adjuvant; D057809:HEK293 Cells; D000882:Haplorhini; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D002351:Carrageenan; D005620:Freund's Adjuvant; C000599953:mavatrep