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目的:DL0805是本实验室发现的具有Rho激酶抑制作用的吲唑类化合物,本研究拟对DL0805结构改造后得到的105个小分子化合物进行体外活性筛选,发现潜在候选药物。方法:利用ELISA方法评价105个化合物的Rho激酶活性抑制作用;采用离体大鼠胸主动脉血管环张力检测系统评价化合物舒张血管作用;利用MTT法,检测化合物对血管平滑肌细胞(VSMC)和人脐静脉内皮细胞(HUVEC)的细胞毒性,并评价化合物对VSMC增殖的抑制作用。结果:经过初筛和复筛,发现5个化合物对Rho激酶活性具有较强的抑制作用;22个化合物对离体血管具有良好的舒张作用;1个化合物对VSMC毒性作用较强;5个化合物对血清诱导的VSMC增殖有一定的抑制作用;3个化合物对HUVEC毒性较强。结论:对DL0805衍生物的生物活性和细胞毒性的系统评价和综合分析,105个化合物中发现5个化合物具有良好的Rho激酶抑制作用、舒张血管活性及较低的细胞毒性,具有继续研究和开发的潜力,其中4个化合物为全新结构,值得进一步研究。
OBJECTIVE: DL0805 is an indazole compound with Rho kinase inhibitory activity discovered in our laboratory. In this study, 105 small molecule compounds obtained after the structural modification of DL0805 were screened in vitro and potential drug candidates were identified. Methods: The inhibitory effect of Rho kinase activity of 105 compounds was evaluated by ELISA. The vasodilating effect of compound was evaluated by the isolated rat thoracic aortic vascular tension test system. The inhibitory effect of the compound on vascular smooth muscle cells (VSMC) and human Cytotoxicity of umbilical vein endothelial cells (HUVECs) was evaluated and the compounds were evaluated for their inhibitory effect on VSMC proliferation. Results: After preliminary screening and re-screening, five compounds were found to have a strong inhibitory effect on Rho kinase activity. Twenty-two compounds had good vasodilatation on isolated blood vessels. One compound had a strong toxic effect on VSMC. Five compounds The proliferation of VSMCs induced by serum was inhibited to a certain extent. The three compounds were highly toxic to HUVECs. Conclusion: The systematic evaluation and comprehensive analysis of biological activity and cytotoxicity of DL0805 derivatives showed that 5 compounds in 105 compounds showed good Rho kinase inhibitory activity, vasodilatory activity and low cytotoxicity with continuous research and development Of the potential, of which four compounds for the new structure, it is worth further study.