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Elsevier, Bioorganic and Medicinal Chemistry, 12(23), p. 2904-2916, 2015

DOI: 10.1016/j.bmc.2015.02.051

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

Journal article published in 2015 by Nicole Mayer, Martina Schweiger ORCID, Michaela-Christina Melcher, Christian Fledelius, Rudolf Zechner ORCID, Robert Zimmermann ORCID, Rolf Breinbauer
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 = 10 μM in an assay with COS7-cell lysate overexpressing murine ATGL.