Veenstra, Siem, Rueeger, Heinrich, Voegtle, Markus, Lueoend, Rainer Martin, Holzer, Philipp, Hurth, Konstanze, Tintelnot-Blomley, Marina, Frederiksen, Mathias, Rondeau, Jean-Michel, Jacobson, Laura, Staufenbiel, Matthias, 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

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.

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
URI:	https://oak.novartis.com/id/eprint/28150