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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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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Med Chem, 2016,
59,
3231-3248.
[DOI no: ]
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PubMed id
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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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