Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors.
A series of [1,2,4]triazolo[4,3-a]pyrazine derivatives (4a-4i) were designed, synthesized and evaluated for their c-Met kinase inhibition and antitumor activity against SNU5 gastric cell line in vitro. Among these compounds, 4d was found to show the highest activity against c-Met and high selectivity against the tumor cells which are believed to be dependent on the c-Met oncogene amplification, because 4d selectively inhibited c-Met while had no effect on other 59 kinases. In vivo efficacy study on human gastric (MKN-45) and human non-small cell lung (NCI-H1993) tumor xenograft in nude mouse demonstrated that 4d·CH3SO3H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound 4d·CH3SO3H was found to have biological half-lives and plasma exposure values higher than those of JNJ-38877605, and its long-term toxicity and acute toxicity turned out to be acceptable, all of which indicates that 4d·CH3SO3H is a desirable drug candidate.
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, China.
Junjun
J
Zhao
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
Lei
L
Fang
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, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
Shaohua
S
Gou
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D066244:Proton Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D011725:Pyridines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
Antitumor; Pharmacokinetic profile; Selectivity; c-Met inhibitors