학술논문
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.
Document Type
Article
Author
Hui Deng; Kooijman, Sander; van den Nieuwendijk, Adrianus M. C. H.; Daisuke Ogasawara; van der Wel, Tom; van Dalen, Floris; Baggelaar, Marc P.; Janssen, Freek J.; van den Berg, Richard J. B. H. N.; den Dulk, Hans; Cravatt, Benjamin F.; Overkleeft, Herman S.; Rensen, Patrick C. N.; van der Stelt, Mario
Source
Subject
*TRIAZOLES
*DIGLYCERIDES
*LIPASE inhibitors
*REFEEDING syndrome
*TARGETED drug delivery
*PREVENTION
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Language
ISSN
0022-2623
Abstract
Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets. [ABSTRACT FROM AUTHOR]