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PDBsum entry 4xkx
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Hydrolase/hydrolase inhibitor
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PDB id
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4xkx
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References listed in PDB file
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Key reference
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Title
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Development of 2-Aminooxazoline 3-Azaxanthenes as orally efficacious β-Secretase inhibitors for the potential treatment of alzheimer'S disease.
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Authors
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J.J.Chen,
Q.Liu,
C.Yuan,
V.Gore,
P.Lopez,
V.Ma,
A.Amegadzie,
W.Qian,
T.C.Judd,
A.E.Minatti,
J.Brown,
Y.Cheng,
M.Xue,
W.Zhong,
T.A.Dineen,
O.Epstein,
J.Human,
C.Kreiman,
I.Marx,
M.M.Weiss,
S.A.Hitchcock,
T.S.Powers,
K.Chen,
P.H.Wen,
D.A.Whittington,
A.C.Cheng,
M.D.Bartberger,
D.Hickman,
J.A.Werner,
H.M.Vargas,
N.E.Everds,
S.L.Vonderfecht,
R.T.Dunn,
S.Wood,
R.T.Fremeau,
R.D.White,
V.F.Patel.
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Ref.
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Bioorg Med Chem Lett, 2015,
25,
767-774.
[DOI no: ]
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PubMed id
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Abstract
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The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of
the most hotly pursued targets for the treatment of Alzheimer's disease. We used
a structure- and property-based drug design approach to identify
2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly
reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the
initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in
a non-human primate cardiovascular safety model.
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