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]-1 H -benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep)
2015; American Chemical Society; Volume: 58; Issue: 9 Linguagem: Inglês
10.1021/acs.jmedchem.5b00132
ISSN1520-4804
AutoresWilliam H. Parsons, Raul R. Calvo, Wing S. Cheung, Yu‐Kai Lee, Sharmila Patel, Jian Liu, Mark A. Youngman, Scott L. Dax, Dennis J. Stone, Na Qin, Tasha L. Hutchinson, Mary Lou Lubin, Sui‐Po Zhang, Michael Finley, Yi Liu, Michael R. Brandt, Christopher M. Flores, Mark R. Player,
Tópico(s)Herbal Medicine Research Studies
ResumoReported 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 Ca2+ 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.
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