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PDBsum entry 4xrz
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4xrz
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References listed in PDB file
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Key reference
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Title
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Utilizing structures of cyp2d6 and bace1 complexes to reduce risk of drug-Drug interactions with a novel series of centrally efficacious bace1 inhibitors.
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Authors
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M.A.Brodney,
E.M.Beck,
C.R.Butler,
G.Barreiro,
E.F.Johnson,
D.Riddell,
K.Parris,
C.E.Nolan,
Y.Fan,
K.Atchison,
C.Gonzales,
A.E.Robshaw,
S.D.Doran,
M.W.Bundesmann,
L.Buzon,
J.Dutra,
K.Henegar,
E.Lachapelle,
X.Hou,
B.N.Rogers,
J.Pandit,
R.Lira,
L.Martinez-Alsina,
P.Mikochik,
J.C.Murray,
K.Ogilvie,
L.Price,
S.M.Sakya,
A.Yu,
Y.Zhang,
B.T.O'Neill.
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Ref.
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J Med Chem, 2015,
58,
3223-3252.
[DOI no: ]
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PubMed id
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Abstract
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In recent years, the first generation of β-secretase (BACE1) inhibitors
advanced into clinical development for the treatment of Alzheimer's disease
(AD). However, the alignment of drug-like properties and selectivity remains a
major challenge. Herein, we describe the discovery of a novel class of potent,
low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5.
Further profiling suggested that a high fraction of the metabolism (>95%) was
due to CYP2D6, increasing the potential risk for victim-based drug-drug
interactions (DDI) and variable exposure in the clinic due to the polymorphic
nature of this enzyme. To guide future design, we solved crystal structures of
CYP2D6 complexes with substrate 5 and its corresponding metabolic product
pyrazole 6, which provided insight into the binding mode and movements between
substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal
structures, we designed and synthesized analogues with reduced risk for DDI,
central efficacy, and improved hERG therapeutic margins.
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