title: Structure-activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL).
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.
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Michaela-Christina
authors.initials: MC
authors.lastname: Melcher
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Fledelius
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria. Electronic address: robert.zimmermann@uni-graz.at.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria. Electronic address: breinbauer@tugraz.at.
authors.forename: Rolf
authors.initials: R
authors.lastname: Breinbauer
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D008049:Lipase; D054852:Small Molecule Libraries; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: Adipose triglyceride lipase; Hydrazones; Inhibitor; Lipid metabolism; Triglycerides