title: 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.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Kasai_Shizuo@takeda.co.jp
authors.forename: Shizuo
authors.initials: S
authors.lastname: Kasai
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.forename: Shinichi
authors.initials: S
authors.lastname: Masada
authors.forename: Jun
authors.initials: J
authors.lastname: Kunitomo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamaura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takami
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogino
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakano
authors.forename: Shuntarou
authors.initials: S
authors.lastname: Ashina
authors.forename: Kaoru
authors.initials: K
authors.lastname: Watanabe
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kaisho
authors.forename: Yumi N
authors.initials: YN
authors.lastname: Imai
authors.forename: Sunghi
authors.initials: S
authors.lastname: Ryu
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nagisa
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.forename: Koki
authors.initials: K
authors.lastname: Kato
authors.forename: Toshiki
authors.initials: T
authors.lastname: Murata
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D001549:Benzamides; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D011804:Quinolines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor