Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6656-60. doi: 10.1016/j.bmcl.2012.08.105. Epub 2012 Sep 7.


The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10 μM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apelin Receptors
  • Cardiovascular Agents / chemistry
  • Cardiovascular Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hepatocytes / drug effects
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Nitrobenzoates / chemical synthesis*
  • Nitrobenzoates / chemistry
  • Nitrobenzoates / pharmacology
  • Protein Binding / drug effects
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Structure-Activity Relationship


  • 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate
  • APLNR protein, human
  • Apelin Receptors
  • Cardiovascular Agents
  • Nitrobenzoates
  • Pyrans
  • Receptors, G-Protein-Coupled