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Bioorg Med Chem. 2016 Aug 15;24(16):3483-93. doi: 10.1016/j.bmc.2016.05.057. Epub 2016 May 30.

Synthesis and biological evaluation of new [1,2,4]triazolo[4,3-a]pyridine derivatives as potential c-Met inhibitors.

Author information

1
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.
2
Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
3
Lianyungang Hongchuang Pharmaceutical Co., Ltd, Lianyungang 222000, China.
4
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.

Abstract

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.

KEYWORDS:

Antitumor; Pharmacokinetic profile; Selectivity; c-Met inhibitors

PMID:
27288183
DOI:
10.1016/j.bmc.2016.05.057
[Indexed for MEDLINE]

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