Discovery of Glycine Sulfonamides as Dual Inhibitors of sn-1-Diacylglycerol Lipase 伪 and 伪/尾-Hydrolase Domain 6

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• 作者：Freek J. Janssen ; Hui Deng ; Marc P. Baggelaar ; Marco Allar脿 ; Tom van der Wel ; Hans den Dulk ; Alessia Ligresti ; Annelot C. M. van Esbroeck ; Ross McGuire ; Vincenzo Di Marzo ; Herman S. Overkleeft ; Mario van der Stelt
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6610-6622
• 全文大小：515K
• ISSN：1520-4804

文摘

sn-1-Diacylglycerol lipase 伪 (DAGL-伪) is the main enzyme responsible for the production of the endocannabinoid 2-arachidonoylglycerol in the central nervous system. Glycine sulfonamides have recently been identified by a high throughput screening campaign as a novel class of inhibitors for this enzyme. Here, we report on the first structure鈥揳ctivity relationship study of glycine sulfonamide inhibitors and their brain membrane proteome-wide selectivity on serine hydrolases with activity-based protein profiling (ABPP). We found that (i) DAGL-伪 tolerates a variety of biaryl substituents, (ii) the sulfonamide is required for inducing a specific orientation of the 2,2-dimethylchroman substituent, and (iii) a carboxylic acid is essential for its activity. ABPP revealed that the sulfonamide glycine inhibitors have at least three off-targets, including 伪/尾-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-伪/ABHD6 inhibitor, which makes this compound a potential lead for the discovery of new molecular therapies for diet-induced obesity and metabolic syndrome.