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Bioorg Med Chem. 2015 Jun 15;23(12):2904-16. doi: 10.1016/j.bmc.2015.02.051. Epub 2015 Mar 5.

Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL).

Author information

1
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
2
Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria.
3
Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
4
Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria. Electronic address: robert.zimmermann@uni-graz.at.
5
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria. Electronic address: breinbauer@tugraz.at.

Abstract

Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50=10μM in an assay with COS7-cell lysate overexpressing murine ATGL.

KEYWORDS:

Adipose triglyceride lipase; Hydrazones; Inhibitor; Lipid metabolism; Triglycerides

PMID:
25778769
PMCID:
PMC4457358
DOI:
10.1016/j.bmc.2015.02.051
[Indexed for MEDLINE]
Free PMC Article

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