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

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 4; pp. 845 - 854
• Main Authors: Liao, Chen, Liu, Yan, Liu, Chunxia, Zhou, Jiaqi, Li, Huilan, Wang, Nasi, Li, Jieming, Liu, Taiyu, Ghaleb, Hesham, Huang, Wenlong, Qian, Hai
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2018; Elsevier
• Subjects: Analgesia; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Phenylquinoline; Physical Sciences; Science & Technology; TRPV1; Phenylquinoline; Analgesia; TRPV1; PATENT LITERATURE; PHARMACOLOGY; RELIEF; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.12.048

Amining to develop pharmacological and improve aqueous solubility, we have identified series of TRPV1 antagonists bearing phenylquinoline moiety, exemplified by the antinoceptive potent and solubility antagonist 37. [Display omitted] 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.