Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.
Clicks: 83
ID: 275495
2021
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.
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| 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 |
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