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

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

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.

Figures
Products