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.
Brian M Fox  1 ,  Hilary P Beck  1 ,  Philip M Roveto  1 ,  Frank Kayser  1 ,  Qingwen Cheng  1 ,  Hannah Dou  1 ,  Toni Williamson  2 ,  James Treanor  1 ,  Hantao Liu  2 ,  Lixia Jin  1 ,  Guifen Xu  1 ,  Ji Ma  1 ,  Songli Wang  1 ,  Steven H Olson  1
Affiliations
  • 1. †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • 2. ‡Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 26061158 DOI: 10.1021/acs.jmedchem.5b00567
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.

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