2-(S)-Phenethylaminothiazolones as Potent, Orally Efficacious Inhibitors of 11-Hydroxysteriod Dehydrogenase Ty

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• 作者：David J. St. Jean ; Jr. ; Chester Yuan ; Eric A. Bercot ; Rod Cupples ; Michelle Chen ; Jenne Fretland ; Clarence Hale ; Randall W. Hungate ; Renee Komorowski ; Murielle Veniant ; Minghan Wang ; Xiping Zhang ; Chri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 8, 2007
• 年：2007
• 卷：50
• 期：3
• 页码：429 - 432
• 全文大小：64K
• 年卷期：v.50,no.3(February 8, 2007)
• ISSN：1520-4804

文摘

11-hydroxysteroid dehydrogenase type 1 (11-HSD1) isthe enzyme that converts cortisone to cortisol. A growing body ofevidence suggests that selective inhibition of 11-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Throughmodification of our initial lead 1, we have discovered trifluoromethylthiazolone 17. This compound had a K_i of 22 nM, possessed low invivo clearance, and showed a 91% inhibition of adipose 11-HSD1enzymatic activity in a mouse ex vivo pharmacodynamic model.