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PDBsum entry 4d8c
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Hydrolase/hydrolase inhibitor
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PDB id
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4d8c
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References listed in PDB file
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Key reference
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Title
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Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-Site app-Cleaving enzyme 1 (bace1) inhibitors: structure-Based design and in vivo reduction of amyloid β-Peptides.
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Authors
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H.Rueeger,
R.Lueoend,
O.Rogel,
J.M.Rondeau,
H.Möbitz,
R.Machauer,
L.Jacobson,
M.Staufenbiel,
S.Desrayaud,
U.Neumann.
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Ref.
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J Med Chem, 2012,
55,
3364-3386.
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PubMed id
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Abstract
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Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors
allowed the rational incorporation of prime- and nonprime-side fragments to a
central core template without any amide functionality. The core scaffold
selection and the structure-activity relationship development were supported by
molecular modeling studies and by X-ray analysis of BACE1 complexes with various
ligands to expedite the optimization of the series. The direct extension from
P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the
enhancement of potency and selectivity over cathepsin D. Restraining the design
and synthesis of compounds to a physicochemical property space consistent with
central nervous system drugs led to inhibitors with improved blood-brain barrier
permeability. Guided by structure-based optimization, we were able to obtain
highly potent compounds such as 60p with enzymatic and cellular IC(50) values of
2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D.
Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180
μmol/kg demonstrated significant reduction of brain Aβ levels.
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Secondary reference #1
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Title
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Structure-Based design, Synthesis and sar of cyclic hydroxyethylamine (hea) bace-1 inhibitors
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Authors
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H.Rueeger,
J.M.Rondeau,
C.Mccarthy,
H.Moebitz,
M.Tintelnot-Blomley,
U.Neumann,
S.Desrayaud.
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Ref.
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bioorg med chem lett, 2011,
21,
1942.
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