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

Bioorganic & Medicinal Chemistry Letters
Siem Jakob VeenstraRainer Machauer

Abstract

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.

Citations

Oct 5, 2019·Chemical Biology & Drug Design·Dhafer S ZinadMohammad Rizki Fadhil Pratama
Jan 26, 2021·Physical Chemistry Chemical Physics : PCCP·Cristian PrivatJaime Rubio-Martinez
Apr 13, 2021·Journal of Medicinal Chemistry·Heinrich RueegerUlf Neumann
Nov 29, 2021·Bioorganic & Medicinal Chemistry Letters·Brandon M TaokaJared N Cumming

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