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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Optimization and evaluation of novel tetrahydropyrido[4,3-d] pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis
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Optimization and evaluation of novel tetrahydropyrido[4,3-d] pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis

机译：新型四氢吡啶[4,3-D]嘧啶衍生物作为ATX抑制剂的心脏和肝纤维化的优化和评价

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摘要

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 vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and log with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while log exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-beta-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated lOg as an excellent anti-hepatofibrosis candidate, which reduced CCI4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：针对纤维化疾病的强化自坦蛋白（ATX）抑制剂旨在开发有效的自坦蛋白（ATX）抑制剂，基于我们以前的研究，设计并合成了一种新的四氢吡啶胺[4,3-D]嘧啶衍生物。将酶测定与对心脏成纤维细胞（CFS）和肝星状细胞（HSC）相结合的抗增殖活性用于初步评估靶化合物的抗纤维化效力，导致两个优异的ATX抑制剂8B和IC50的原木。纳米摩拉（24.6和15.3nm）中的值。不同，8B对CFS的抑制率为81.5％的最突出的化合物，而目录表现出对T-HSC / CL-6细胞的最大抑制率为83.7％。在体内进一步评估药理学，胶原沉积测定表明8b的抑制TGF-β介导的心脏纤维化的突出能力。同时，H＆E和Masson染色的小鼠肝脏验证的候选物作为优异的抗肝纤维化候选物，其降低了CCI4诱导的肝纤维化水平突出。此外，分子结合模型鉴定了8B和ATX之间的基本相互作用，其与SARS一致。 （c）2019年Elsevier Masson SAS。版权所有。

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  • 来源
  • 作者

    Jiang Nan; Zhou Yuhong; Zhu Minglin; Zhang Junlong; Cao Meng; Lei Hongrui; Guo Ming; Gong Ping; Su Guangyue; Zhai Xin;

  • 作者单位

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Harbin Med Univ State Prov Key Labs Biomed Pharmaceut China Key Lab Cardiovasc Res Minist Educ;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

    Shenyang Pharmaceut Univ Sch Funct Food &

    Wine Shenyang 110016 Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    ATX; THPPs; Semicarbazones; Cardiac fibrosis; Hepaticfibrosis;

    机译：ATX;THPPS;半咔唑;心肌纤维化;肝纤维化;

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