Referenced in: none

Automatically associated channels: Kir2.3 , Kv11.1

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.

Authors: Shizuo Kasai, Makoto Kamata, Shinichi Masada, Jun Kunitomo, Masahiro Kamaura, Tomohiro Okawa, Kazuaki Takami, Hitomi Ogino, Yoshihide Nakano, Shuntarou Ashina, Kaoru Watanabe, Tomoko Kaisho, Yumi N Imai, Sunghi Ryu, Masaharu Nakayama, Yasutaka Nagisa, Shiro Takekawa, Koki Kato, Toshiki Murata, Nobuhiro Suzuki, Yuji Ishihara

Journal, date & volume: J. Med. Chem., 2012 May 10 , 55, 4336-51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22490048

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.