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

  • ChemMedChem. 2015 Feb;10(2):253-65. doi: 10.1002/cmdc.201402453.
Jayendra Z Patel  1 ,  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
Affiliations
  • 1. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio (Finland). [email protected].
PMID: 25504894 DOI: 10.1002/cmdc.201402453
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.

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