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

Rueeger, Heinrich, Lueoend, Rainer Martin, Machauer, Rainer, Veenstra, Siem, Holzer, Philipp, Hurth, Konstanze, Voegtle, Markus, Frederiksen, Mathias, Rondeau, Jean-Michel, Tintelnot-Blomley, Marina, Jacobson, Laura, Staufenbiel, Matthias, Laue, Grit and Neumann, Ulf (2021) Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360. Journal of Medicinal Chemistry, 64 (8). pp. 4677-4696. ISSN 0022-26231520-4804


Starting from lead compound 4, 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 CF3 group delivered an excellent pharmacological profile with a pKa 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 N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens.

Item Type: Article
Date Deposited: 12 May 2021 00:45
Last Modified: 12 May 2021 00:45


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