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Eur J Med Chem. 2016 Aug 8;118:290-8. doi: 10.1016/j.ejmech.2016.04.021. Epub 2016 Apr 10.

New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.

Author information

1
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada.
2
Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, NB E2L 4L5, Canada.
3
National Research Council of Canada, 1200 Montreal Road, Ottawa, ON, Canada.
4
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada. Electronic address: mohamed.touaibia@umoncton.ca.

Abstract

Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities.

KEYWORDS:

Adipocytes; Adipose triglyceride lipase (ATGL); Atglistatin; Inhibitors; Lipolysis; Structure–activity relationship

PMID:
27155760
DOI:
10.1016/j.ejmech.2016.04.021
[Indexed for MEDLINE]

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