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PDBsum entry 6bfe
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Hydrolase/hydrolase inhibitor
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PDB id
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6bfe
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References listed in PDB file
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Key reference
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Title
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Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences.
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Authors
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A.B.Bueno,
J.Agejas,
H.Broughton,
R.Dally,
T.B.Durham,
J.F.Espinosa,
R.González,
P.J.Hahn,
A.Marcos,
R.Rodríguez,
G.Sanz,
J.F.Soriano,
D.Timm,
P.Vidal,
H.C.Yang,
J.R.Mccarthy.
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Ref.
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J Med Chem, 2017,
60,
9807-9820.
[DOI no: ]
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PubMed id
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Abstract
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NMR conformational analysis of a hydroxyethylamine peptide isostere developed as
an aspartic protease inhibitor shows that it is a flexible architecture.
Cyclization to form pyrrolidines, piperidines, or morpholines results in a
preorganization of the whole system in solution. The resulting conformation is
similar to the conformation of the inhibitor in the active site of BACE-1. This
entropic gain results in increased affinity for the enzyme when compared with
the acyclic system. For morpholines 27 and 29, the combination of steric and
electronic factors is exploited to orient substituents toward S1, S1', and S2'
pockets both in the solution and in the bound states. These highly preorganized
molecules proved to be the most potent compounds of the series. Additionally,
the morpholines, unlike the pyrrolidine and piperidine analogues, have been
found to be brain penetrant BACE-1 inhibitors.
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