Discovery of Orally Efficacious Melanin-Concentrating Hormone Receptor-1 Antagonists as Antiobesity Agents. Synthesis, SAR, and Biological Evaluation of Bicyclo[3.1.0]hexyl Ureas

• Published in: Journal of medicinal chemistry Vol. 49; no. 7; pp. 2294 - 2310
• Main Authors: McBriar, Mark D, Guzik, Henry, Shapiro, Sherry, Paruchova, Jaroslava, Xu, Ruo, Palani, Anandan, Clader, John W, Cox, Kathleen, Greenlee, William J, Hawes, Brian E, Kowalski, Timothy J, O'Neill, Kim, Spar, Brian D, Weig, Blair, Weston, Daniel J, Farley, Constance, Cook, John
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.04.2006; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Biological Availability; Body Weight - drug effects; Brain - metabolism; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Eating - drug effects; Half-Life; Hormones. Endocrine system; Life Sciences & Biomedicine; Male; Medical sciences; Obesity - drug therapy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - pharmacology; Piperazines - chemical synthesis; Piperazines - pharmacology; Radioligand Assay; Rats; Receptors, Somatostatin - antagonists & inhibitors; Receptors, Somatostatin - metabolism; Science & Technology; Structure-Activity Relationship; Tissue Distribution; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology; THERAPEUTICS; HORMONE-RECEPTOR-1 ANTAGONISTS; KETONES; OBESITY; BENZAMIDES; REAGENTS; CYCLOPROPANATION; INDAZOLES; MICE; IDENTIFICATION; Obesity; Rat; Rodentia; Nutrition disorder; Oral administration; Vertebrata; Mammalia; Treatment; Structure activity relation; Mouse; Animal; Organic fluorine compounds; Melanin concentrating hormone; Benzonitrile derivatives; Ureas; Antagonist; Piperazine derivatives; Pharmacokinetics; Chemical synthesis; Biological receptor; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050886n

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure−activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.