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Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors

Veenstra, Siem and Rueeger, Heinrich and Voegtle, Markus and Lueoend, Rainer Martin and Holzer, Philipp and Hurth, Konstanze and Tintelnot-Blomley, Marina and Frederiksen, Mathias and Rondeau, Jean-Michel and Jacobson, Laura and Staufenbiel, Matthias and Neumann, Ulf and Machauer, Rainer (2018) Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorganic and Medicinal Chemistry Letters, 28 (12). pp. 2195-2200. ISSN 14643405


New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.

Item Type: Article
Keywords: Alzheimer's disease Amino-1,4-oxazines BACE-1 P-gp pKa
Date Deposited: 09 Aug 2018 00:45
Last Modified: 09 Aug 2018 00:45


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