Piperazine Sulfonamides as Potent, Selective, and Orally Available 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors with Efficacy in the Rat Cortisone-Induced Hyperinsulinemia Model
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- 作者：Jason Xiang ; Zhao-Kui Wan ; Huan-Qiu Li ; Manus Ipek ; Eva Binnun ; Jill Nunez ; Lihren Chen ; John C. McKew ; Tarek S. Mansour ; Xin Xu ; Vipin Suri ; May Tam ; Yuzhe Xing ; Xiangping Li ; Seung Hahm ; James Tobin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：July 24, 2008
- 年：2008
- 卷：51
- 期：14
- 页码：4068-4071
- 全文大小：125K
- 年卷期：v.51,no.14(July 24, 2008)
- ISSN：1520-4804
文摘
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11β-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure−activity relationship, and in vivo evaluation of piperazine sulfonamides as 11β-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11β-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.