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Publication Abstract from PubMed

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 Abeta levels in mice, rats, and dogs in acute and chronic treatment regimens.

Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Holzer P, Hurth K, Voegtle M, Frederiksen M, Rondeau JM, Tintelnot-Blomley M, Jacobson LH, Staufenbiel M, Laue G, Neumann U J Med Chem. 2021 Apr 22;64(8):4677-4696. doi: 10.1021/acs.jmedchem.0c02143. Epub , 2021 Apr 12. PMID:33844524^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.