Parsons William H, Calvo Raul R, Cheung Wing, Lee Yu-Kai, Patel Sharmila, Liu Jian, Youngman Mark A, Dax Scott L, Stone Dennis, Qin Ning, Hutchinson Tasha, Lubin Mary Lou, Zhang Sui-Po, Finley Michael, Liu Yi, Brandt Michael R, Flores Christopher M, Player Mark R
J Med Chem. 2015 May 14;58(9):3859-74. doi: 10.1021/acs.jmedchem.5b00132. Epub 2015 Apr 15.
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.
本文报道了一类基于苯并[d]咪唑平台构建的TRPV1拮抗剂的设计、合成及药理学特性，该平台由联芳基酰胺先导物衍生而来。这种设计由三个部分组成：连接到苯并[d]咪唑平台上的2-取代5-苯基头基，其在2位连接到苯基尾基。对该设计的优化导致了化合物4（马伐曲普）的鉴定，其包含三氟甲基-苯基-乙烯基尾基。在使用表达重组人TRPV1通道的细胞进行的TRPV1功能测定中，化合物4拮抗辣椒素诱导的Ca(2+)内流，IC50值为4.6 nM。在完全弗氏佐剂和角叉菜胶诱导的热超敏模型中，化合物4表现出完全疗效，ED80值分别为7.8和0.5 mg/kg，分别对应血浆水平270.8和9.2 ng/mL。基于其优异的药理学和安全性，化合物4（马伐曲普）被选择用于疼痛治疗的临床开发。
