Aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists—Increasing selectivity over hERG

• Published in: Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (3), p.819-822
• Main Authors: Meyers, Kenneth M., Méndez-Andino, José L., Colson, Anny-Odile, Warshakoon, Namal C., Wos, John A., Mitchell, Maria C., Hodge, Karen M., Howard, Jeremy M., Ackley, David C., Holbert, Jerry K., Mittelstadt, Scott W., Dowty, Martin E., Obringer, Cindy M., Reizes, Ofer, Hu, X. Eric
• Format: Article
• Language: English
• Subjects: Aminomethyl tetrahydronaphthalene ketopiperazines; Animals; Biological and medical sciences; Dogs; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - drug effects; General and cellular metabolism. Vitamins; Heart Rate - drug effects; hERG; Hormones. Endocrine system; Humans; Indicators and Reagents; MCH-R1 antagonists; Medical sciences; Melanin-concentrating hormone; Mice; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Obesity; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - pharmacology; Potassium Channel Blockers - pharmacology; QTc prolongation; Receptors, Somatostatin - antagonists & inhibitors; Weight Loss - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.10.052

A direct correlation between hERG binding and QTc prolongation was established for this series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. A direct correlation between hERG binding and QTc prolongation was established for a series of aminomethyl tetrahydronaphthalene ketopiperazine MCH-R1 antagonists. Compounds within this class with greater selectivity over hERG were developed. Compound 4h proved to have the best profile, with MCH-R1 K i = 16 nm and hERG IC 50 = 25 μM.