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Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-isopropyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-08-03 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01045 Zhen Wang 1, 2 , Yali Zhang , Daniel M. Pinkas 3 , Alice E. Fox 3 , Jinfeng Luo 2 , Huocong Huang 4 , Shengyang Cui 2 , Qiuping Xiang 2 , Tingting Xu , Qiuju Xun 2 , Dongsheng Zhu 2 , Zhengchao Tu 2 , Xiaomei Ren 1 , Rolf A. Brekken 4 , Alex N. Bullock 3 , Guang Liang , Ke Ding 1 , Xiaoyun Lu 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-08-03 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01045 Zhen Wang 1, 2 , Yali Zhang , Daniel M. Pinkas 3 , Alice E. Fox 3 , Jinfeng Luo 2 , Huocong Huang 4 , Shengyang Cui 2 , Qiuping Xiang 2 , Tingting Xu , Qiuju Xun 2 , Dongsheng Zhu 2 , Zhengchao Tu 2 , Xiaomei Ren 1 , Rolf A. Brekken 4 , Alex N. Bullock 3 , Guang Liang , Ke Ding 1 , Xiaoyun Lu 1
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Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 proteins with Kd values of 7.9 and 8.0 nM; potently inhibited the kinases with IC50 values of 9.4 and 20.4 nM, respectively; and was significantly less potent for a panel of 403 wild-type kinases at 1.0 μM. DDR1- and DDR2-kinase inhibition by 5n was validated by Western-blotting analysis in primary human lung fibroblasts. The compound also dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release in vitro and exhibited promising in vivo anti-inflammatory effects in an LPS-induced-acute-lung-injury (ALI) mouse model. Compound 5n may serve as a lead compound for new anti-inflammatory drug discovery.
中文翻译：
3-（咪唑并[1,2 - a ]吡嗪-3-基乙炔基）-4-异丙基-N-（3-（（4-甲基哌嗪-1-基）甲基）-5-的设计，合成及生物学评价（三氟甲基）苯基）苯甲酰胺作为盘状结构域受体1和2的双重抑制剂。
Discoidin域受体1和2（DDR1和DDR2）是抗炎药物发现的新潜在靶标。设计并优化了一系列杂环炔基苯并亚胺以抑制DDR1和DDR2。最有前途的化合物之一5n与DDR1和DDR2蛋白紧密结合，K d值为7.9和8.0 nM；有效抑制激酶，IC 50值分别为9.4和20.4 nM；并且对于1.0μM的一组403种野生型激酶的效力明显较低。DDR1和DDR2激酶抑制5n通过Western-blotting分析验证了原代人肺成纤维细胞的有效性。该化合物还在体外剂量依赖性抑制脂多糖（LPS）诱导的白介素6（IL-6）释放，并在LPS诱导的急性肺损伤（ALI）小鼠模型中表现出有希望的体内抗炎作用。化合物5n可用作新的抗炎药发现的先导化合物。
更新日期：2018-08-03
中文翻译：
3-（咪唑并[1,2 - a ]吡嗪-3-基乙炔基）-4-异丙基-N-（3-（（4-甲基哌嗪-1-基）甲基）-5-的设计，合成及生物学评价（三氟甲基）苯基）苯甲酰胺作为盘状结构域受体1和2的双重抑制剂。
Discoidin域受体1和2（DDR1和DDR2）是抗炎药物发现的新潜在靶标。设计并优化了一系列杂环炔基苯并亚胺以抑制DDR1和DDR2。最有前途的化合物之一5n与DDR1和DDR2蛋白紧密结合，K d值为7.9和8.0 nM；有效抑制激酶，IC 50值分别为9.4和20.4 nM；并且对于1.0μM的一组403种野生型激酶的效力明显较低。DDR1和DDR2激酶抑制5n通过Western-blotting分析验证了原代人肺成纤维细胞的有效性。该化合物还在体外剂量依赖性抑制脂多糖（LPS）诱导的白介素6（IL-6）释放，并在LPS诱导的急性肺损伤（ALI）小鼠模型中表现出有希望的体内抗炎作用。化合物5n可用作新的抗炎药发现的先导化合物。
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