7b1e

BACE1 IN COMPLEX WITH compound 3 (NB-641)

spinqualitylabelsall models 7b1e, resolution 1.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.62Å Ligands: SKW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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