Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine β-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation

[Display omitted] The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2018-04, Vol.28 (6), p.1111-1115
Hauptverfasser: Low, Jonathan D., Bartberger, Michael D., Cheng, Yuan, Whittington, Doug, Xue, Quifen, Wood, Stephen, Allen, Jennifer R., Minatti, Ana E.
Format: Artikel
Sprache:eng
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Zusammenfassung:[Display omitted] The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aβ40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.01.056