7B1E

BACE1 IN COMPLEX WITH compound 3 (NB-641)

Summary for 7B1E

• Entry DOI: 10.2210/pdb7b1e/pdb
• Descriptor: Beta-secretase 1, ~{N}-[3-[(4~{S})-2-azanyl-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: beta-secretase; bace1; memapsin2; aspartic acid proteinase; alzheimer's disease; enzyme inhibitor complex; structure-based drug design, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 45182.65

Authors

Rondeau, J.M.,Wirth, E. (deposition date: 2020-11-24, release date: 2021-04-28, Last modification date: 2021-05-05)

Primary citation

Rueeger, H.,Lueoend, R.,Machauer, R.,Veenstra, S.J.,Holzer, P.,Hurth, K.,Voegtle, M.,Frederiksen, M.,Rondeau, J.M.,Tintelnot-Blomley, M.,Jacobson, L.H.,Staufenbiel, M.,Laue, G.,Neumann, U.
Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.
J.Med.Chem., 64:4677-4696, 2021

PubMed 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.

PubMed: 33844524
DOI: 10.1021/acs.jmedchem.0c02143

Experimental method

X-RAY DIFFRACTION (1.62 Å)