Phenylquinoline Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of 1-(2-phenylquinoline-4-carbonyl)-N-(4- (trifluoromethyl)phenyl)pyrrolidine-3-carboxamide

Publication date: Available online 30 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Chen Liao, Yan Liu, Chunxia Liu, Jiaqi Zhou, Huilan Li, Nasi Wang, Jieming Li, Taiyu Liu, Hesham Ghaleb, Wenlong Huang, Hai Qian
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a Phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl−phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca²⁺ influx, with an IC50 value of 10.2 nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.

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