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PDBsum entry 4b1d
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References listed in PDB file
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Key reference
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Title
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New aminoimidazoles as β-Secretase (bace-1) inhibitors showing amyloid-β (Aβ) lowering in brain.
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Authors
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Y.Gravenfors,
J.Viklund,
J.Blid,
T.Ginman,
S.Karlström,
J.Kihlström,
K.Kolmodin,
J.Lindström,
S.Von berg,
F.Von kieseritzky,
K.Bogar,
C.Slivo,
B.M.Swahn,
L.L.Olsson,
P.Johansson,
S.Eketjäll,
J.Fälting,
F.Jeppsson,
K.Strömberg,
J.Janson,
F.Rahm.
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Ref.
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J Med Chem, 2012,
55,
9297-9311.
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PubMed id
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Abstract
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Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the
treatment of Alzheimer's disease. Synthetic methods, crystal structures, and
structure-activity relationships for target activity, permeability, and hERG
activity are reported and discussed. Compound (S)-1m was one of the most
promising compounds in this report, with high potency in the cellular assay and
a good overall profile. When guinea pigs were treated with compound (S)-1m, a
concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma,
brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5
h after oral dosing (100 μmol/kg). The results presented highlight the
potential of this new class of BACE-1 inhibitors with good target potency and
with low effect on hERG, in combination with a fair CNS exposure in vivo.
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