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PDBsum entry 4zsq
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Hydrolase/hydrolase inhibitor
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PDB id
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4zsq
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References listed in PDB file
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Key reference
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Title
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Preparation and biological evaluation of conformationally constrained bace1 inhibitors.
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Authors
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L.L.Winneroski,
M.A.Schiffler,
J.A.Erickson,
P.C.May,
S.A.Monk,
D.E.Timm,
J.E.Audia,
J.P.Beck,
L.N.Boggs,
A.R.Borders,
R.D.Boyer,
R.A.Brier,
K.J.Hudziak,
V.J.Klimkowski,
P.Garcia losada,
B.M.Mathes,
S.L.Stout,
B.M.Watson,
D.J.Mergott.
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Ref.
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Bioorg Med Chem Lett, 2015,
23,
3260-3268.
[DOI no: ]
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PubMed id
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Abstract
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The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1
research efforts, fragment screening revealed that bicyclic thiazine 3 had low
millimolar activity against BACE1. Analysis of the co-crystal structure of 3
suggested that potency could be increased through extension toward the S3 pocket
and through conformational constraint of the thiazine core. Pursuit of
S3-binding groups produced low micromolar inhibitor 6, which informed the
S3-design for constrained analogs 7 and 8, themselves prepared via independent,
multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8
is described.
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