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.
MeSH terms
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Animals
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Biological Assay / methods*
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Brain / cytology
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Brain / drug effects*
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Brain / metabolism
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Molecular Structure
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Oxazepines / chemical synthesis
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Oxazepines / pharmacokinetics
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Oxazepines / pharmacology*
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Phagocytosis / drug effects*
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Plaque, Amyloid / metabolism*
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Pyridones / chemical synthesis
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Pyridones / pharmacokinetics
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Pyridones / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors*
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Structure-Activity Relationship
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Tissue Distribution
Substances
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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
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Oxazepines
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Pyridones
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Receptors, Prostaglandin E, EP2 Subtype