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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
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2017-12-30 , DOI: 10.1016/j.bmc.2017.12.048
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.



中文翻译:

苯喹啉瞬态受体潜在的香草酸1拮抗剂治疗疼痛:1-(2-苯基喹啉-4-羰基)-N-(4-(三氟甲基)苯基)吡咯烷-3-羧酰胺的发现

本文报道的是设计,合成和药理学表征的一类在从喹古芬铅进化而来的苯基喹啉平台上构建的TRPV1拮抗剂。该设计包括三个部分:连接到脂族羧酰胺的苯基喹啉头基,该端基被束缚在苯基尾基上。该设计的优化导致鉴定出37个,其中包括一个吡咯烷连接子和一个三氟甲基-苯基尾巴。在TRPV1功能测定中,使用表达hTRPV1的细胞,有37种拮抗辣椒素诱导的Ca 2+内流,IC 50值为10.2 nM。在完整的小鼠镇痛模型中,37在不同的疼痛模型中,与阳性对照BCTC相比,它们显示出更好的抗伤害感受活性。所有这些结果表明,可以考虑将37种药物作为抗伤害性药物进一步开发的主要候选药物。

更新日期:2017-12-30
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