Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors Academic Article uri icon

Overview

MeSH Major

  • Carbamates
  • Enzyme Inhibitors
  • Monoacylglycerol Lipases
  • Thiadiazoles

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.

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4471478

Digital Object Identifier (DOI)

  • 10.1002/cmdc.201402453

PubMed ID

  • 25504894

Additional Document Info

start page

  • 253

end page

  • 65

volume

  • 10

number

  • 2