Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors.

Jayendra Z Patel, Tapio J Nevalainen, Juha R Savinainen, Yahaya Adams, Tuomo Laitinen, Robert S Runyon, Miia Vaara, Stephen Ahenkorah, Agnieszka A Kaczor, Dina Navia-Paldanius, Mikko Gynther, Niina Aaltonen, Amit A Joharapurkar, Mukul R Jain, Abigail S Haka, Frederick R Maxfield, Jarmo T Laitinen, Teija Parkkari

Index: ChemMedChem 10(2) , 253-65, (2015)

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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.© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.