A Selective Prostaglandin E2 Receptor Subtype 2 (EP2) Antagonist Increases the Macrophage-Mediated Clearance of Amyloid-Beta Plaques
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- 作者：Brian M. Fox ; Hilary P. Beck ; Philip M. Roveto ; Frank Kayser ; Qingwen Cheng ; Hannah Dou ; Toni Williamson ; James Treanor ; Hantao Liu ; Lixia Jin ; Guifen Xu ; Ji Ma ; Songli Wang ; Steven H. Olson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：July 9, 2015
- 年：2015
- 卷：58
- 期：13
- 页码：5256-5273
- 全文大小：851K
- ISSN：1520-4804
文摘
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 鈭?000-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鈥揇awley 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.