4J0Z

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4S,5R)-2-amino-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide

Summary for 4J0Z

• Entry DOI: 10.2210/pdb4j0z/pdb
• Related: 4J0P 4J0T 4J0V 4J0Y
• Descriptor: Beta-secretase 1, SODIUM ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: protease inhibitor, 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: 46067.45

Authors

Kuglstatter, A.,Stihle, M. (deposition date: 2013-01-31, release date: 2013-05-01, Last modification date: 2024-10-30)

Primary citation

Hilpert, H.,Guba, W.,Woltering, T.J.,Wostl, W.,Pinard, E.,Mauser, H.,Mayweg, A.V.,Rogers-Evans, M.,Humm, R.,Krummenacher, D.,Muser, T.,Schnider, C.,Jacobsen, H.,Ozmen, L.,Bergadano, A.,Banner, D.W.,Hochstrasser, R.,Kuglstatter, A.,David-Pierson, P.,Fischer, H.,Polara, A.,Narquizian, R.
beta-Secretase (BACE1) Inhibitors with High In Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer s Disease
J.Med.Chem., 56:3980-3995, 2013

PubMed Abstract: An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

PubMed: 23590342
DOI: 10.1021/jm400225m

Experimental method

X-RAY DIFFRACTION (2.13 Å)