期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 7, 页码 2127-2142出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm101340q
关键词
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资金
- Shanghai Commission of Science and Technology [10410702600, 10JC1417100, 10dz1910104]
- National Science and Technology [2009ZX09301-001, 2009ZX09103-062]
- Natural Science Foundation of China [30725046]
- Program of Shanghai Subject Chief Scientist [10XD1405100]
By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a-c, 211, and 27a-c were identified as the most potent c-Met inhibitors with IC50 of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68-69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.
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