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

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

Affiliation

  • 1 School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio (Finland). jayendra.patel@uef.fi.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z