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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hydrazones / chemical synthesis
  • Hydrazones / chemistry*
  • Hydrazones / pharmacology*
  • Lipase / antagonists & inhibitors*
  • Lipase / metabolism
  • Lipid Metabolism / drug effects
  • Mice
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Triglycerides / metabolism


  • Enzyme Inhibitors
  • Hydrazones
  • Small Molecule Libraries
  • Triglycerides
  • Lipase
  • PNPLA2 protein, mouse