Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.

Clicks: 201
ID: 275495
2021
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Abstract
Starting from lead compound , the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF group delivered an excellent pharmacological profile with a p of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent -(3-((3,6)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (), able to reduce significantly A levels in mice, rats, and dogs in acute and chronic treatment regimens.
Reference Key
rueeger2021synthesisjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Rueeger, Heinrich;Lueoend, Rainer;Machauer, Rainer;Veenstra, Siem J;Holzer, Philipp;Hurth, Konstanze;Voegtle, Markus;Frederiksen, Mathias;Rondeau, Jean-Michel;Tintelnot-Blomley, Marina;Jacobson, Laura H;Staufenbiel, Matthias;Laue, Grit;Neumann, Ulf;
Journal Journal of medicinal chemistry
Year 2021
DOI
10.1021/acs.jmedchem.0c02143
URL
Keywords
Antimicrobial endophytes cytotoxic fusarium oxysporum vicia faba

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