Synthesis and biological evaluation of new [1, 2, 4]triazolo[4, 3-a]pyridine derivatives as potential c-Met inhibitors. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Zhao, Junjun; Fang, Lei; Zhang, Xiaobing; Liang, Yan; Gou, Shaohua
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3483
• Page End: 3493
• Publication Date: 2016-08-15
• Subjects: Antitumor -- c-Met inhibitors -- Selectivity -- Pharmacokinetic profile; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.057
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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, because4d 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 that4d ·CH3 SO3 H had a better inhibiting activity than SGX-523 in a dose-dependent manner. When tested in mice, compound4d ·CH3 SO3 H 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 that4d ·CH3 SO3 H is a desirable drug candidate.