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 <b>1</b>, 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 <b>1</b> was discontinued because <b>1</b> 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 <b>1</b> and a docking study were conducted. Replacement of the terminal <i>p</i>-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 <i>N</i>-{3-[(1<i>R</i>)-1-{[2-(acetylamino)­ethyl]­amino}­ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)­benzamide <b>(</b><i><b>R</b></i><b>)-10h</b>. The compound <b>(</b><i><b>R</b></i><b>)-10h</b> 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 <b>(</b><i><b>R</b></i><b>)-10h</b> was performed to determine the molecule’s absolute configuration