Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China.
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China.
Eur J Med Chem. 2020 May 15;194:112236. doi: 10.1016/j.ejmech.2020.112236. Epub 2020 Mar 19.
N-(4-Tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide (BCTC) is a potent and extensively studied urea-based TRPV1 antagonist. Although BCTC was effective in alleviating chronic pain in rats, it showed obvious hyperthermia side-effect and unsatisfactory pharmacokinetic profile, therefore, it was not developed further. In order to enrich the structural types of urea-based TRPV1 antagonists, two series of novel analogs, in which the pyridine ring of BCTC was replaced with a mildly basic pyrimidine ring or 1,2,3,4-tetrahydro-β-carboline scaffold, were designed and synthesized. Advancing the structure-activity relationship of these two series led to the discovery of N-(4-methoxyphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxamide (7o), with an improved pharmacological and tolerability profile compared with the lead compound BCTC.
N-(4-叔丁基苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺（BCTC）是一种强效的、广泛研究的基于脲的 TRPV1 拮抗剂。尽管 BCTC 在缓解大鼠慢性疼痛方面有效，但它表现出明显的高热副作用和不理想的药代动力学特征，因此没有进一步开发。为了丰富基于脲的 TRPV1 拮抗剂的结构类型，设计并合成了两个系列的新型类似物，其中 BCTC 的吡啶环被碱性较弱的嘧啶环或 1,2,3,4-四氢-β-咔啉骨架取代。深入研究这两个系列的构效关系，发现了 N-(4-甲氧基苯基)-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-甲酰胺（7o），与先导化合物 BCTC 相比，其具有改善的药理学和耐受性特征。
