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PDBsum entry 4j1c
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Hydrolase/hydrolase inhibitor
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PDB id
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4j1c
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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Med Chem, 2013,
56,
3980-3995.
[DOI no: ]
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PubMed id
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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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