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

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• 作者：Francis X. Tavares ; Kamal A. Al-Barazanji ; Eric C. Bigham ; Michael J. Bishop ; Christy S. Britt ; David L. Carlton ; Paul L. Feldman ; Aaron S. Goetz ; Mary K. Grizzle ; Yu C. Guo ; Anthony L. Handlon ; Dona
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 30, 2006
• 年：2006
• 卷：49
• 期：24
• 页码：7095 - 7107
• 全文大小：408K
• 年卷期：v.49,no.24(November 30, 2006)
• ISSN：1520-4804

文摘

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