Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

J Med Chem. 2016 Dec 8;59(23):10738-10749. doi: 10.1021/acs.jmedchem.6b01427. Epub 2016 Nov 18.


Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Administration, Oral
  • Animals
  • Biological Availability
  • Crystallography, X-Ray
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lactams / administration & dosage
  • Lactams / chemical synthesis
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship
  • Tissue Distribution


  • Enzyme Inhibitors
  • Lactams
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PLA2G7 protein, human