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PDBsum entry 5hdu
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Hydrolase/hydrolase inhibitor
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PDB id
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5hdu
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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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Bace-1 incomplex with (7ar)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5- fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2h-pyrrolo[3, 4-d]pyrimidin-2-iminium
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Structure:
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Beta-secretase 1. Chain: a, b. Fragment: unp residues 41-454. Synonym: aspartyl protease 2,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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1.58Å
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R-factor:
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0.193
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R-free:
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0.214
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Authors:
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P.Orth
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Key ref:
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M.Mandal
et al.
(2016).
Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates.
J Med Chem,
59,
3231-3248.
PubMed id:
DOI:
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Date:
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05-Jan-16
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Release date:
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16-Mar-16
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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.
387 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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DOI no:
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J Med Chem
59:3231-3248
(2016)
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PubMed id:
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Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates.
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M.Mandal,
Y.Wu,
J.Misiaszek,
G.Li,
A.Buevich,
J.P.Caldwell,
X.Liu,
R.D.Mazzola,
P.Orth,
C.Strickland,
J.Voigt,
H.Wang,
Z.Zhu,
X.Chen,
M.Grzelak,
L.A.Hyde,
R.Kuvelkar,
P.T.Leach,
G.Terracina,
L.Zhang,
Q.Zhang,
M.S.Michener,
B.Smith,
K.Cox,
D.Grotz,
L.Favreau,
K.Mitra,
I.Kazakevich,
B.A.McKittrick,
W.Greenlee,
M.E.Kennedy,
E.M.Parker,
J.N.Cumming,
A.W.Stamford.
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ABSTRACT
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We describe successful efforts to optimize the in vivo profile and address
off-target liabilities of a series of BACE1 inhibitors represented by 6 that
embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold.
Employing structure-based design, truncation of the cyanophenyl group of 6 that
binds in the S3 pocket of BACE1 followed by modification of the thienyl group in
S1 was pursued. Optimization of the pyrimidine substituent that binds in the
S2'-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier
analogues in this series and imparted high BACE1 affinity. These efforts
resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly
lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a
single oral dose. Compound 9 represents a unique molecular shape among BACE
inhibitors reported to potently lower central Aβ in nonrodent preclinical
species.
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Links
