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PDBsum entry 4j1h
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Hydrolase/hydrolase inhibitor
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PDB id
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4j1h
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of bace-1 in complex with 5-cyano-pyridine-2- carboxylic acid [3-((4s,6r)-2-amino-4-methyl-6-trifluoromethyl-5,6- dihydro-4h-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide
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Structure:
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Beta-secretase 1. Chain: a. Synonym: aspartyl protease 2, asp2, asp 2, beta-site amyloid precursor protein cleaving enzyme 1, beta-site app cleaving enzyme 1, memapsin-2, membrane-associated aspartic protease 2. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.20Å
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R-factor:
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0.188
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R-free:
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0.236
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Authors:
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A.Kuglstatter,M.Stihle
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Key ref:
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H.Hilpert
et al.
(2013).
β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease.
J Med Chem,
56,
3980-3995.
PubMed id:
DOI:
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Date:
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01-Feb-13
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Release date:
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01-May-13
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PROCHECK
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Headers
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References
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P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
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Seq:
Struc:
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501 a.a.
370 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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J Med Chem
56:3980-3995
(2013)
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PubMed id:
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β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease.
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H.Hilpert,
W.Guba,
T.J.Woltering,
W.Wostl,
E.Pinard,
H.Mauser,
A.V.Mayweg,
M.Rogers-Evans,
R.Humm,
D.Krummenacher,
T.Muser,
C.Schnider,
H.Jacobsen,
L.Ozmen,
A.Bergadano,
D.W.Banner,
R.Hochstrasser,
A.Kuglstatter,
P.David-Pierson,
H.Fischer,
A.Polara,
R.Narquizian.
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ABSTRACT
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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.
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