title: A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques.
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.
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Beck
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Roveto
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Hannah
authors.initials: H
authors.lastname: Dou
authors.affiliation: ‡Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Toni
authors.initials: T
authors.lastname: Williamson
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: James
authors.initials: J
authors.lastname: Treanor
authors.affiliation: ‡Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Hantao
authors.initials: H
authors.lastname: Liu
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Songli
authors.initials: S
authors.lastname: Wang
authors.affiliation: †Amgen South San Francisco, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D058225:Plaque, Amyloid / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C000601733:4-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo(f)(1,4)oxazepin-4(5H)-yl)methyl)pyridin-2(1H)-one; D010077:Oxazepines; D011728:Pyridones; D058307:Receptors, Prostaglandin E, EP2 Subtype