6C2I

Structure of Bace-1 (Beta-Secretase) in complex with : N-(3-((1R,5S,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

Summary for 6C2I

• Entry DOI: 10.2210/pdb6c2i/pdb
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: bace, beta-secretase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46854.77

Authors

Sickmier, E.A. (deposition date: 2018-01-08, release date: 2018-02-21, Last modification date: 2024-10-30)

Primary citation

Low, J.D.,Bartberger, M.D.,Cheng, Y.,Whittington, D.,Xue, Q.,Wood, S.,Allen, J.R.,Minatti, A.E.
Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation.
Bioorg. Med. Chem. Lett., 28:1111-1115, 2018

PubMed Abstract: The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aβ levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.

PubMed: 29426770
DOI: 10.1016/j.bmcl.2018.01.056

Experimental method

X-RAY DIFFRACTION (1.95 Å)