Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
School of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China.
Bioorg Med Chem. 2018 Feb 15;26(4):845-854. doi: 10.1016/j.bmc.2017.12.048. Epub 2017 Dec 30.
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 Ca influx, with an IC 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.
本文报道了一类 TRPV1 拮抗剂的设计、合成和药理特性，该拮抗剂构建在辛可芬先导化合物的苯并喹啉平台上。该设计由三部分组成：连接脂肪族羧酰胺的苯并喹啉头部基团，通过苯尾部基团连接。对该设计的优化导致了 37 的鉴定，其包含吡咯烷连接子和三氟甲基-苯尾部。在 TRPV1 功能测定中，使用表达 hTRPV1 的细胞，37 拮抗辣椒素诱导的 Ca 内流，IC 值为 10.2nM。在完整的小鼠镇痛模型中，37 在各种疼痛模型中比阳性对照 BCTC 表现出更好的镇痛活性。所有这些结果表明，37 可以被认为是进一步开发镇痛药物的潜在先导化合物。
