Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors

作者：Jing, Tongfei; Miao, Xiuqi; Jiang, Feng; Guo, Ming; Xing, Lingyun; Zhang, Junlong; Zuo, Daiying; Lei, Hongrui; Zhai, Xin^*

来源：Bioorganic & Medicinal Chemistry, 2018, 26(8): 1784-1796.

DOI：10.1016/j.bmc.2018.02.023

• THPPs
• Semicarbazones
• ATX
• EGFR
• Inhibitor
• IPF-LC

In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 mu M at 10 mu g/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-beta and TNF-alpha in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.

• 出版日期2018-5-1
• 单位沈阳药科大学