Discovery, Optimization, and Biological Evaluation of 5-(2-(Trifluoromethyl)phenyl)indazoles as a Novel Class of Transient Receptor Potential A1 (TRPA1) Antagonists
Discovery, Optimization, and Biological Evaluation of 5-(2-(Trifluoromethyl)phenyl)indazoles as a Novel Class of Transient Receptor Potential A1 (TRPA1) Antagonists
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DOI：
10.1021/jm401986p
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发表时间：
2014-06-26
影响因子：
7.3
通讯作者：
Tully, David C.
中科院分区：
文献类型：
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作者：
Rooney, Lisa;Vidal, Agnes;Tully, David C.
高通量筛选活动鉴定5-（2-氯苯基）吲唑化合物4为瞬时受体电位A1（TRPA 1）离子通道的拮抗剂，IC 50 = 1.23 μ M。Hit领导的药物化学优化建立了吲唑环系统周围的SAR，证明苯环2位的三氟甲基与吲唑环6位的各种取代基的组合极大地改善了体外活性。进一步的先导优化导致化合物31的鉴定，化合物31是TRPA 1的有效和选择性的体外拮抗剂（IC 50 = 0.015 μ M），其在啮齿动物中具有中等的口服生物利用度，并在几种啮齿动物炎性疼痛模型中显示出稳健的体内活性。
A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 mu M. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 mu M), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain.