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PDBsum entry 4fsl
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Hydrolase/inhibitor
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PDB id
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4fsl
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References listed in PDB file
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Key reference
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Title
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Acyl guanidine inhibitors of β-Secretase (bace-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- And solution-Phase library synthesis.
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Authors
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S.W.Gerritz,
W.Zhai,
S.Shi,
S.Zhu,
J.H.Toyn,
J.E.Meredith,
L.G.Iben,
C.R.Burton,
C.F.Albright,
A.C.Good,
A.J.Tebben,
J.K.Muckelbauer,
D.M.Camac,
W.Metzler,
L.S.Cook,
R.Padmanabha,
K.A.Lentz,
M.J.Sofia,
M.A.Poss,
J.E.Macor,
L.A.Thompson.
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Ref.
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J Med Chem, 2012,
55,
9208-9223.
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PubMed id
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Abstract
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This report describes the discovery and optimization of a BACE-1 inhibitor
series containing an unusual acyl guanidine chemotype that was originally
synthesized as part of a 6041-membered solid-phase library. The synthesis of
multiple follow-up solid- and solution-phase libraries facilitated the
optimization of the original micromolar hit into a single-digit nanomolar BACE-1
inhibitor in both radioligand binding and cell-based functional assay formats.
The X-ray structure of representative inhibitors bound to BACE-1 revealed a
number of key ligand:protein interactions, including a hydrogen bond between the
side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group,
and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl
substituent. Following subcutaneous administration in rats, an acyl guanidine
inhibitor with single-digit nanomolar activity in cells afforded good plasma
exposures and a dose-dependent reduction in plasma Aβ levels, but poor brain
exposure was observed (likely due to Pgp-mediated efflux), and significant
reductions in brain Aβ levels were not obtained.
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