☆ 4.5 Article

Optimization of 1,2,5-Thiadiazole Carbamates as Potent and Selective ABHD6 Inhibitors

CHEMMEDCHEM (2015)

期刊

CHEMMEDCHEM

卷 10, 期 2, 页码 253-265

出版社

WILEY-V C H VERLAG GMBH

DOI: 10.1002/cmdc.201402453

关键词

ABHD6; 2-arachidonoylglycerol; cannabinoids; homology modeling; receptors; 1,2,5-thiadiazole carbamates

类别

Chemistry, Medicinal Pharmacology & Pharmacy

资金

Graduate School of Drug Design, University of East Finland
Academy of Finland [139140, 127653, 139620]
Drug Discovery and Chemical Biology (DDCB) Consortium
Biocenter Finland
US National Institutes of Health (NIH) [R37-DK27083]
Marie Curie Intra-European Fellowship
Interdisciplinary Center for Mathematical and Computational Modeling (ICM), Warsaw, Poland [G30-18]
Academy of Finland (AKA) [127653, 127653] Funding Source: Academy of Finland (AKA)

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摘要

At present, inhibitors of alpha/beta-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 similar to 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.

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