Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors
Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors
复制标题
四氢异喹啉-7-甲酰胺衍生物作为新型选择性盘状蛋白结构域受体 1 (DDR1) 抑制剂
DOI：
10.1021/acsmedchemlett.6b00497
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发表时间：
2017
影响因子：
4.2
通讯作者：
Ding Ke
中科院分区：
文献类型：
--
作者：
Wang Zhen;Zhang Yali;Bartual Sergio G.;Luo Jinfeng;Xu Tingting;Du Wenting;Xun Qiuju;Tu Zhengchao;Brekken Rolf A.;Ren Xiaomei;Bullock Alex N.;Liang Guang;Lu Xiaoyun;Ding Ke
急性肺损伤（acute lung injury，ALI）是严重肺部炎症的致命症状。盘状结构域受体1（DDR 1）是抗炎药物发现的新的潜在靶点。发现一种新的基于四氢异喹啉-7-甲酰胺的选择性DDR 1受体7ae与DDR 1蛋白紧密结合，并有效抑制其激酶功能，Kd值为2.2 nM，IC 50值为6.6 nM。该化合物剂量依赖性地抑制小鼠原代腹腔巨噬细胞（MPM）中脂多糖（LPS）诱导的白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）释放。此外，7ae在LPS诱导的小鼠ALI模型中也表现出有希望的体内抗炎作用。据我们所知，这是关于小分子DDR 1抑制剂治疗ALI的潜在应用的第一个“概念验证”研究。
Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti-inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor7aewas discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with aKdvalue of 2.2 nM and an IC50value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) release in mouse primary peritoneal macrophages (MPMs). In addition,7aealso exhibited promisingin vivoanti-inflammatory effects in a LPS-induced mouse ALI model. To the best of our knowledge, this is the first “proof of concept” investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI.