Title:Novel [1,2,4] Triazol [4,3-a] Pyridine Derivatives as Potential Selective c-Met Inhibitors with Improved Pharmacokinetic Properties
VOLUME: 17 ISSUE: 8
Author(s):Junjun Zhao, Shaohua Gou*, Xiaobing Zhang, Yan Liang and Lei Fang*
Affiliation:Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189
Keywords:Antitumor, c-Met inhibitors, selectivity, pharmacokinetic properties, [1, 2, 4] Triazol [4, 3-a] pyridine derivatives, apoptosis.
Abstract:Aims: Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized.
Method: The target compounds, especially 4aa, showed potent activity to inhibit c-Met both in an enzyme assay
and a cellular assay. The comprehensive screening for the inhibition of 60 different kinases revealed that 4aa could
selectively inhibit c-Met while had no effect on other kinases, indicating 4aa is an excellent c-Met selective
inhibitor.
Result: The flow cytometry studies found that 4aa had a similar behavior to the positive control SGX-523 in terms
of causing the tumor cell apoptosis and blocking cell-cycle progression. More importantly, 4aa showed much
better pharmacokinetic properties than SGX-523. Altogether, the findings suggested the target compounds may be
potential anti-tumor drug candidates.
