A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques

J Med Chem. 2015 Jul 9;58(13):5256-73. doi: 10.1021/acs.jmedchem.5b00567. Epub 2015 Jun 24.

Abstract

A high-throughput screen resulted in the discovery of benzoxazepine 1, an EP2 antagonist possessing low microsomal stability and potent CYP3A4 inhibition. Modular optimization of lead compound 1 resulted in the discovery of benzoxazepine 52, a molecule with single-digit nM binding affinity for the EP2 receptor and significantly improved microsomal stability. It was devoid of CYP inhibition and was ∼4000-fold selective against the other EP receptors. Compound 52 was shown to have good PK properties in CD-1 mice and high CNS permeability in C57Bl/6s mice and Sprague-Dawley rats. In an ex vivo assay, it demonstrated the ability to increase the macrophage-mediated clearance of amyloid-beta plaques from brain slices in a dose-dependent manner.

MeSH terms

  • Animals
  • Biological Assay / methods*
  • Brain / cytology
  • Brain / drug effects*
  • Brain / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Oxazepines / chemical synthesis
  • Oxazepines / pharmacokinetics
  • Oxazepines / pharmacology*
  • Phagocytosis / drug effects*
  • Plaque, Amyloid / metabolism*
  • Pyridones / chemical synthesis
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • 4-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo(f)(1,4)oxazepin-4(5H)-yl)methyl)pyridin-2(1H)-one
  • Oxazepines
  • Pyridones
  • Receptors, Prostaglandin E, EP2 Subtype