title: Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.
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 CB1receptor. 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.
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Hui
authors.identifier: 0000-0003-0899-4188
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kooijman
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogasawara
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Wel
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: van Dalen
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Marc P
authors.identifier: 0000-0002-9784-6250
authors.initials: MP
authors.lastname: Baggelaar
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Freek J
authors.initials: FJ
authors.lastname: Janssen
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: den Dulk
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Benjamin F
authors.identifier: 0000-0001-5330-3492
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University , 2333 CC Leiden, The Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
mesh_terms: D000818:Animals; D004435:Eating; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005215:Fasting; D057809:HEK293 Cells; D006801:Humans; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors*; D051379:Mice; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014508:Urea / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D014508:Urea; D008071:Lipoprotein Lipase