喹唑啉衍生物的构效关系研究促成强效表皮生长因子受体T790M抑制剂的发现。
Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors.
作者信息
Zhang Long, Yang Yingying, Zhou Haojie, Zheng Qingmei, Li Yuhao, Zheng Shansong, Zhao Shuyong, Chen Dong, Fan Chuanwen
机构信息
Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
出版信息
Eur J Med Chem. 2015 Sep 18;102:445-63. doi: 10.1016/j.ejmech.2015.08.026. Epub 2015 Aug 17.
We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
我们已经开发了一系列6,7-二取代-4-(芳基氨基)喹唑啉衍生物，它们作为不可逆的表皮生长因子受体（EGFR）抑制剂发挥作用，并且这些化合物表现出优异的酶抑制效力。与阿法替尼相比，其中一些对H1975细胞（EGFR-T790M）显示出显著增强的活性。此外，优化后的化合物7q和8f还表现出良好的药代动力学特征、口服生物利用度，以及在无毒剂量下对H1975和HCC827异种移植瘤优异的体内疗效。基于针对EGFR-T790M耐药性改善的安全性和有效性，7q和8f是有前景的进一步研究候选物。
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