Efficacious 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors in the Diet-Induced Obesity Mouse Model

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• 作者：Zhao-Kui Wan ; Eva Chenail ; Jason Xiang ; Huan-Qiu Li ; Manus Ipek ; Joel Bard ; Kristine Svenson ; Tarek S. Mansour ; Xin Xu ; Xianbin Tian ; Vipin Suri ; Seung Hahm ; Yuzhe Xing ; Christian E. Johnson ; Xiangpin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 10, 2009
• 年：2009
• 卷：52
• 期：17
• 页码：5449-5461
• 全文大小：1106K
• 年卷期：v.52,no.17(September 10, 2009)
• ISSN：1520-4804

文摘

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11β-hydroxysteroid dehydrogenase type I (11β-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11β-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11β-HSD1 inhibition may be a valid target for the treatment of diabetes.