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PDBsum entry 4joo
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Hydrolase/hydrolase inhibitor
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PDB id
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4joo
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Spirocyclic beta-site amyloid precursor protein cleaving enzyme 1 (bace1) inhibitors
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Structure:
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Beta-secretase 1. Chain: a. Fragment: bace1 57-453. 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. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.80Å
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R-factor:
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0.189
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R-free:
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0.218
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Authors:
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G.P.A.Vigers,D.Smith
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Key ref:
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K.W.Hunt
et al.
(2013).
Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species.
J Med Chem,
56,
3379-3403.
PubMed id:
DOI:
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Date:
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18-Mar-13
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Release date:
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10-Apr-13
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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.
402 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 6 residue positions (black
crosses)
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DOI no:
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J Med Chem
56:3379-3403
(2013)
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PubMed id:
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Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species.
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K.W.Hunt,
A.W.Cook,
R.J.Watts,
C.T.Clark,
G.Vigers,
D.Smith,
A.T.Metcalf,
I.W.Gunawardana,
M.Burkard,
A.A.Cox,
M.K.Geck Do,
D.Dutcher,
A.A.Thomas,
S.Rana,
N.C.Kallan,
R.K.DeLisle,
J.P.Rizzi,
K.Regal,
D.Sammond,
R.Groneberg,
M.Siu,
H.Purkey,
J.P.Lyssikatos,
A.Marlow,
X.Liu,
T.P.Tang.
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ABSTRACT
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A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ),
a peptide of 36-43 amino acids that is likely a primary driver of
neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1
and γ-secretase; therefore, inhibition of BACE1 represents an attractive
therapeutic target to slow or prevent Alzheimer's disease. Herein we describe
BACE1 inhibitors with limited molecular flexibility and molecular weight that
decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we
explore structure-activity relationships of core changes, P3 moieties, and Asp
binding functional groups in order to optimize BACE1 affinity, cathepsin D
selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea
pig and rat, we demonstrate a PK/PD relationship between free drug
concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure
led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.
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Links
