Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 15; pp. 4274 - 4279
• Main Authors: Berglund, Susanne, Egner, Bryan J., Gradén, Henrik, Gradén, Joakim, Morgan, David G.A., Inghardt, Tord, Giordanetto, Fabrizio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.08.2009; Elsevier
• Subjects: Animal Feed; Animals; Biological and medical sciences; Cell Line; Chemistry, Pharmaceutical - methods; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Feeding Behavior; General and cellular metabolism. Vitamins; Humans; Inhibitory Concentration 50; MCH; MCH-R1 antagonists; Medical sciences; Melanin-concentrating hormone; Models, Chemical; Obesity - drug therapy; Obesity, hERG, hERG inhibitors; Pharmacology. Drug treatments; Piperidines - chemistry; Protein Binding; Rats; Receptors, Pituitary Hormone - antagonists & inhibitors; Urea - analogs & derivatives; Urea - chemistry; Obesity, hERG, hERG inhibitors; MCH-R1 antagonists; MCH; Melanin-concentrating hormone; Imidazole derivatives; Nitrogen heterocycle; Isozyme; Toxicity; Ionic channel; Pyrrole derivatives; hERG inhibitors; Enzymatic activity; Anti-obesity agent; Structure activity relation; Piperidine derivatives; Melanin concentrating hormone; Antagonist; Chemical synthesis; Obesity; Unspecific monooxygenase; hERG; Enzyme; Cytochrome P450; Benzene derivatives; In vitro; Affinity; Drug-metabolizing enzyme; Fluorine Organic compounds; Oxidoreductases; Circulatory system; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.05.066

Strategies aiming at reducing hERG-associated liabilities in a class of potent MCH-R1 antagonists are presented. The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.