title: Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase α and α/β-hydrolase domain 6.
abstract: sn-1-Diacylglycerol lipase α (DAGL-α) 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-activity 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-α 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 α/β-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-α/ABHD6 inhibitor, which makes this compound a potential lead for the discovery of new molecular therapies for diet-induced obesity and metabolic syndrome.
authors.affiliation: Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University , Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Freek J
authors.initials: FJ
authors.lastname: Janssen
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.forename: Marc P
authors.initials: MP
authors.lastname: Baggelaar
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.forename: Tom
authors.initials: T
authors.lastname: van der Wel
authors.forename: Hans
authors.initials: H
authors.lastname: den Dulk
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Annelot C M
authors.initials: AC
authors.lastname: van Esbroeck
authors.forename: Ross
authors.initials: R
authors.lastname: McGuire
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D020543:Proteome / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000594997:N-((2,2-dimethylchroman-6-yl)sulfonyl)-N-(4-phenoxybenzyl)glycine; D020543:Proteome; D013449:Sulfonamides; C540878:ABHD6 protein, human; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D005998:Glycine