127007-34-5Relevant articles and documents
Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3- aminomethylquinolines: Reducing human ether-a-go-go-related gene (hERG) associated liabilities
Kasai, Shizuo,Kamata, Makoto,Masada, Shinichi,Kunitomo, Jun,Kamaura, Masahiro,Okawa, Tomohiro,Takami, Kazuaki,Ogino, Hitomi,Nakano, Yoshihide,Ashina, Shuntarou,Watanabe, Kaoru,Kaisho, Tomoko,Imai, Yumi N.,Ryu, Sunghi,Nakayama, Masaharu,Nagisa, Yasutaka,Takekawa, Shiro,Kato, Koki,Murata, Toshiki,Suzuki, Nobuhiro,Ishihara, Yuji
supporting information; experimental part, p. 4336 - 4351 (2012/07/01)
Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino} ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
