Potent, Selective, and Orally Efficacious Antagonists of Melanin-Concentrating Hormone Receptor 1

• Published in: Journal of medicinal chemistry 2006-11, Vol.49 (24), p.7095-7107
• Main Authors: Tavares, Francis X, Al-Barazanji, Kamal A, Bigham, Eric C, Bishop, Michael J, Britt, Christy S, Carlton, David L, Feldman, Paul L, Goetz, Aaron S, Grizzle, Mary K, Guo, Yu C, Handlon, Anthony L, Hertzog, Donald L, Ignar, Diane M, Lang, Daniel G, Ott, Ronda J, Peat, Andrew J, Zhou, Hui-Qiang
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Biological Availability; CHO Cells; Cricetinae; Cricetulus; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - drug effects; Ether-A-Go-Go Potassium Channels - physiology; Genes, Reporter; Half-Life; Hormones. Endocrine system; Humans; Medical sciences; Mice; Mice, Obese; Models, Molecular; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, Somatostatin - antagonists & inhibitors; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060572f

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure−activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure−activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pK as and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.