| Autor: |
Parsons WH, Calvo RR, Cheung W, Lee YK, Patel S, Liu J, Youngman MA, Dax SL, Stone D, Qin N, Hutchinson T, Lubin ML, Zhang SP, Finley M, Liu Y, Brandt MR, Flores CM, Player MR |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2015 May 14; Vol. 58 (9), pp. 3859-74. Date of Electronic Publication: 2015 Apr 15. |
| DOI: |
10.1021/acs.jmedchem.5b00132 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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