Discovery of cyclopentane- and cyclohexane- trans-1,3-diamines as potent melanin-concentrating hormone receptor 1 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 15; pp. 4232 - 4241
• Main Authors: Giordanetto, Fabrizio, Karlsson, Olle, Lindberg, Jan, Larsson, Lars-Olof, Linusson, Anna, Evertsson, Emma, Morgan, David G.A., Inghardt, Tord
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2007; Elsevier
• Subjects: Biological and medical sciences; Cyclohexanes - chemistry; Cyclopentanes - chemistry; Diamines - chemistry; Diamines - pharmacology; General and cellular metabolism. Vitamins; Hormones. Endocrine system; Humans; MCH; MCH-R1 antagonists; Medical sciences; Melanin-concentrating hormone receptor; Models, Molecular; Obesity; Pharmacology. Drug treatments; Receptors, Somatostatin - antagonists & inhibitors; Melanin-concentrating hormone receptor; MCH-R1 antagonists; Obesity; MCH; Optimization; Structure activity relation; Trans stereoisomer; Melanin concentrating hormone; Antagonist; Chemical synthesis; Nutritional status; Biological receptor; Rodentia; Nutrition disorder; In vitro; Diamine; In vivo; Hydrolysis resistance; Vertebrata; Mammalia; Mouse; Animal; Affinity; Pharmacokinetics; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.034

The optimization of a HTS-derived lead compound into a potent and metabolically stable MCH-R1 antagonist is presented. We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists.