6FGY

Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4

Summary for 6FGY

• Entry DOI: 10.2210/pdb6fgy/pdb
• Descriptor: Beta-secretase 1, ~{N}-[3-[(3~{R})-5-azanyl-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: oxazine, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44482.87

Authors

Rondeau, J.-M.,Bourgier, E. (deposition date: 2018-01-11, release date: 2018-06-06, Last modification date: 2024-10-16)

Primary citation

Veenstra, S.J.,Rueeger, H.,Voegtle, M.,Lueoend, R.,Holzer, P.,Hurth, K.,Tintelnot-Blomley, M.,Frederiksen, M.,Rondeau, J.M.,Jacobson, L.,Staufenbiel, M.,Neumann, U.,Machauer, R.
Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.
Bioorg. Med. Chem. Lett., 28:2195-2200, 2018

PubMed Abstract: New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.

PubMed: 29764741
DOI: 10.1016/j.bmcl.2018.05.003

Experimental method

X-RAY DIFFRACTION (1.54 Å)