Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.

Autor:	Deng H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Kooijman S; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands., van den Nieuwendijk AM; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Ogasawara D; Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States., van der Wel T; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., van Dalen F; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Baggelaar MP; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Janssen FJ; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., van den Berg RJ; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., den Dulk H; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Cravatt BF; Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States., Overkleeft HS; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands., Rensen PC; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands., van der Stelt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Jan 12; Vol. 60 (1), pp. 428-440. Date of Electronic Publication: 2016 Dec 19.
DOI:	10.1021/acs.jmedchem.6b01482
Abstrakt:	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 CB 1 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 CB 1 -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.
Databáze:	MEDLINE
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