Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL). Issue 12 (15th June 2015)

• Record Type: Journal Article
• Authors: Mayer, Nicole; Schweiger, Martina; Melcher, Michaela-Christina; Fledelius, Christian; Zechner, Rudolf; Zimmermann, Robert; Breinbauer, Rolf
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 12(2015)
• Page Start: 2904
• Page End: 2916
• Publication Date: 2015-06-15
• Subjects: Adipose triglyceride lipase -- Hydrazones -- Inhibitor -- Lipid metabolism -- Triglycerides; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.051
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.