Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Nicole Mayer; Martina Schweiger; Elisabeth Fuchs; Anna K Migglautsch; Carina Doler; Gernot F Grabner; Matthias Romauch; Michaela-Christina Melcher; Rudolf Zechner; Robert Zimmermann; Rolf Breinbauer

doi:10.1016/j.bmc.2020.115610

Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)

Bioorg Med Chem. 2020 Aug 15;28(16):115610. doi: 10.1016/j.bmc.2020.115610. Epub 2020 Jul 4.

Affiliations

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, A-8010 Graz, Austria; BIOTECHMED Graz, A-8010, Austria.
³ Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31, A-8010 Graz, Austria.
⁴ Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31, A-8010 Graz, Austria; BIOTECHMED Graz, A-8010, Austria. Electronic address: robert.zimmermann@uni-graz.at.
⁵ Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria; BIOTECHMED Graz, A-8010, Austria. Electronic address: breinbauer@tugraz.at.

PMID: 32690265
DOI: 10.1016/j.bmc.2020.115610

Abstract

High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.

Keywords: Atglistatin; Lipolysis; NAFLD; PNPLA2; Small molecule inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Discovery
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Lipase / antagonists & inhibitors*
Lipase / chemistry
Lipase / metabolism
Lipolysis / drug effects
Mice
Phenylurea Compounds / chemistry*
Phenylurea Compounds / pharmacology*
Structure-Activity Relationship
Triglycerides / blood

Substances

Enzyme Inhibitors
Phenylurea Compounds
Triglycerides
atglistatin
Lipase
PNPLA2 protein, mouse