Novel [1,2,4] Triazol [4,3-a] Pyridine Derivatives as Potential Selective c-Met Inhibitors with Improved Pharmacokinetic Properties.
OBJECTIVE
Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized.


METHODS
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.


RESULTS
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.
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Junjun
J
Zhao
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Shaohua
S
Gou
Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, China.
Xiaobing
X
Zhang
Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, China.
Yan
Y
Liang
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Lei
L
Fang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019859:Proto-Oncogene Proteins c-met; C023666:pyridine
2; 3-a] pyridine derivatives; 4] Triazol [4; Antitumor; [1; apoptosis; c-Met inhibitors; pharmacokinetic properties; selectivity