Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent

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, 21l, and 27a-c were identified as the most potent c-Met inhibitors with IC(50) 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.