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PDBsum entry 4b1c
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PDB id:
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Hydrolase
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Title:
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New aminoimidazoles as bace-1 inhibitors: from rational design to ab- lowering in brain
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Structure:
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Beta-secretase 1. Chain: a. Fragment: residues 56-445. Synonym: aspartyl protease 2, asp2, asp 2, beta-site amyloid precursor protein cleaving enzyme 1, beta-site app cleaving enzyme 1, memapsin-2, membrane-associated aspartic protease 2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.95Å
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R-factor:
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0.191
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R-free:
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0.245
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Authors:
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F.Rahm,J.Blid,T.Ginman,S.Karlstrom,J.Kihlstrom,K.Kolmodin, J.Lindstrom,S.Von Berg,F.Von Kieseritzky,C.Slivo,B.Swahn,J.Viklund, L.Olsson,P.Johansson,S.Eketjall,J.Falting,F.Jeppsson,K.Stromberg, J.Janson,Y.Gravenfors
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Key ref:
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Y.Gravenfors
et al.
(2012).
New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.
J Med Chem,
55,
9297-9311.
PubMed id:
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Date:
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10-Jul-12
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Release date:
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10-Oct-12
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PROCHECK
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Headers
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References
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P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
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Seq:
Struc:
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501 a.a.
375 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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J Med Chem
55:9297-9311
(2012)
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PubMed id:
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New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.
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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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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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