Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11¦Â-hydroxysteroid dehydrogenase type 1

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• 作者：Guangxin Xia^a ; ^b ; Lin Liu^a ; ^b ; Mengzhu Xue^a ; Haiyan Liu^b ; Jianxin Yu^b ; Ping Li^b ; Qian Chen^b ; Bing Xiong^a ; ^{bxiong@mail.shcnc.ac.cn} ; Xuejun Liu^b ; Jingkang Shen^a ; ^b ; ^{jkshen@mail.shcnc.ac.cn}
• 关键词：11¦Â-HSD1 ; Inhibitor ; Sulfonamide ; Diabetes ; Docking
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 出版时间：6 July, 2012
• 年：2012
• 卷：358
• 期：1
• 页码：46-52
• 全文大小：1836 K

文摘

Several classes of non-steroid 11¦Â-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11¦Â-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11¦Â-HSD1 with an IC₅₀ of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11¦Â-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71 % and 63 % inhibition in adipose and liver tissue at 1 h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3 h. This study not only provides compounds as novel h11¦Â-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11¦Â-HSD1 inhibitors suitable for in vivo evaluation in rodent models.