Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain.
Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain.
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DOI：
10.1016/j.ejmech.2022.114413
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发表时间：
2022-04
影响因子：
6.7
通讯作者：
Yuxi Wang;Xiaoyue Hu;Han Huang;Zefang Jin;Jian Gao;Yi Guo;Yi Zhong;Zhongtang Li;Xiaolin Zong;Kewei Wang;L. Zhang;Zhenming Liu
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作者：
Yuxi Wang;Xiaoyue Hu;Han Huang;Zefang Jin;Jian Gao;Yi Guo;Yi Zhong;Zhongtang Li;Xiaolin Zong;Kewei Wang;L. Zhang;Zhenming Liu
目前的疼痛管理在很大程度上限于阿片类药物和非甾体抗炎药。开发新的镇痛药物对于解决慢性疼痛患者未满足的医疗需求仍然很重要。钙激活的氯离子通道anoctamin-1（ANO 1）是一个潜在的镇痛靶点。ANO 1被外周感觉神经元中的伤害性刺激激活，并进一步诱导神经去极化。ANO 1的下调可减少炎症和神经损伤引起的痛觉过敏和异常性疼痛。在这里，我们开发了一系列4-芳基噻吩-3-羧酸衍生物的概念验证研究的ANO 1靶向镇痛。这些努力导致化合物DFBTA，4-（4-氯苯基）-2-（2，5-二氟苯甲酰氨基）噻吩-3-羧酸的鉴定，其显示出显著的ANO 1抑制，IC 50为24 nM。DFBTA显示出非常弱的细胞毒性、心脏毒性和急性毒性（HEK 293增殖IC 50> 30 μM，hERG IC 50> 30 μM，小鼠最小致死剂量，MLD>1000 mg/kg），以及优异的药代动力学性质，口服生物利用度>75%，脑渗透性很小（脑/血浆<1.5%）。最后，在动物模型中评价ANO 1抑制剂的镇痛效果。DFBTA在完全弗氏佐剂、福尔马林和辣椒素诱导的所有炎性疼痛模型中显示出与临床药物相当的疗效。这些工作提供了一个有用的工具化合物和有前途的结果ANO 1靶向镇痛剂的开发。
Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC50of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50> 30 μM, hERG IC50> 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma). Finally, the analgesic efficacy of ANO1 inhibitor was evaluated in animal models. DFBTA shown comparable efficacy to clinical drugs in all inflammatory pain models induced by complete Freund's adjuvant, formalin, and capsaicin. These works provide a useful tool compound and promising results for ANO1-targenting analgesic development.