Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease

J Med Chem. 2019 May 9;62(9):4312-4324. doi: 10.1021/acs.jmedchem.8b02004. Epub 2019 Mar 26.


5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / chemistry
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacokinetics
  • 5-Lipoxygenase-Activating Protein Inhibitors / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Clinical Trials, Phase I as Topic
  • Coronary Artery Disease / drug therapy*
  • Dogs
  • Drug Discovery
  • Female
  • Humans
  • Leukotriene B4 / antagonists & inhibitors
  • Male
  • Molecular Structure
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • 5-Lipoxygenase-Activating Protein Inhibitors
  • AZD5718
  • Pyrazoles
  • Leukotriene B4