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Title
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Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.
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Authors
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R.Machauer,
S.Veenstra,
J.M.Rondeau,
M.Tintelnot-Blomley,
C.Betschart,
U.Neumann,
P.Paganetti.
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Ref.
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Bioorg Med Chem Lett, 2009,
19,
1361-1365.
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PubMed id
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Abstract
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The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to
create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray
co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a
series of macrocyclic analogues 3a-h covalently linking the P1 and P3
side-chains. These inhibitors show improved enzymatic potency over their
open-chain analogue. Inhibitor 3h also shows activity in a cellular system.
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