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
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DOI：
10.1021/acs.jmedchem.5b00567
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发表时间：
2015-07-09
影响因子：
7.3
通讯作者：
Olson, Steven H.
中科院分区：
文献类型：
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作者：
Fox, Brian M.;Beck, Hilary P.;Olson, Steven H.
一个高通量的筛选导致苯并氧氮杂卓1，EP 2拮抗剂具有低微粒体稳定性和有效的CYP 3A 4抑制的发现。先导化合物1的模块优化导致苯并氧氮杂卓52的发现，该分子对EP 2受体具有单位数nM的结合亲和力，并显著改善微粒体稳定性。它缺乏对EP受体的抑制作用，并且对其他EP受体的选择性类似于4000倍。化合物52显示在CD-1小鼠中具有良好的PK性质，在C57 Bl/6s小鼠和Sprague-Dawley大鼠中具有高CNS渗透性。在离体测定中，它证明了以剂量依赖性方式增加巨噬细胞介导的从脑切片中清除淀粉样蛋白-β斑块的能力。
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 similar to 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.