Optimization and evaluation of novel tetrahydropyrido[4,3-d]pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis.
Optimization and evaluation of novel tetrahydropyrido[4,3-d]pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis.
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DOI：
10.1016/j.ejmech.2019.111904
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发表时间：
2019-11
影响因子：
6.7
通讯作者：
Nan Jiang;Yuhong Zhou;Minglin Zhu;Junlong Zhang;Meng Cao;Hongrui Lei;Ming-juan Guo;P. Gong-
中科院分区：
文献类型：
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作者：
Nan Jiang;Yuhong Zhou;Minglin Zhu;Junlong Zhang;Meng Cao;Hongrui Lei;Ming-juan Guo;P. Gong-
为了开发有效的自分泌运动因子（autotaxin，ATX）抑制剂，在前期研究的基础上，设计并合成了一系列新型四氢吡啶并[4，3-d]嘧啶衍生物。酶促试验结合体外抗心脏成纤维细胞（CF）和肝星状细胞（HSC）增殖活性用于初步评价目标化合物的抗纤维化效力，产生两种突出的ATX化合物8和10 g，IC 50值在纳摩尔范围内（24.6和15.3 nM）。其中8b对CFs的抑制率最高，为81.5%; 10 g对t-HSC/Cl-6细胞的抑制率最高，为83.7%。在进一步的体内药理学评价中，胶原沉积实验证明8b具有显著的抑制TGF-β介导的心脏纤维化的能力。同时，小鼠肝脏H&E染色和Masson染色实验证实10 gas是一种良好的抗肝纤维化候选物，其显著降低CCl 4诱导的肝纤维化水平。此外，分子结合模型确定了8条带ATX之间的相互作用，与SAR相吻合。
Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC)in vitrowere applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors8band10gwith the IC50values in a nanomolar range (24.6 and 15.3 nM). Differently,8bwas the most prominent compound against CFs with inhibition ratio of 81.5%, while10gexhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluationsin vivo, collagen deposition assay demonstrated the conspicuous capacity of8bto suppress TGF-β-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated10gas an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between8band ATX which was coincided with the SARs.