title: Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors.
abstract: At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 =44 nM) and showed ∼230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio (Finland). jayendra.patel@uef.fi.
authors.forename: Jayendra Z
authors.initials: JZ
authors.lastname: Patel
authors.forename: Tapio J
authors.initials: TJ
authors.lastname: Nevalainen
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.forename: Yahaya
authors.initials: Y
authors.lastname: Adams
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.forename: Robert S
authors.initials: RS
authors.lastname: Runyon
authors.forename: Miia
authors.initials: M
authors.lastname: Vaara
authors.forename: Stephen
authors.initials: S
authors.lastname: Ahenkorah
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
authors.forename: Niina
authors.initials: N
authors.lastname: Aaltonen
authors.forename: Amit A
authors.initials: AA
authors.lastname: Joharapurkar
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Haka
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D008049:Lipase; D008994:Monoacylglycerol Lipases; D013830:Thiadiazoles; D000099252:Fatty Acid Amide Hydrolases; C000601544:4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate; C540878:ABHD6 protein, human
keywords: 1,2,5-thiadiazole carbamates; 2-arachidonoylglycerol; ABHD6; cannabinoids; homology modeling; receptors