BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate A beta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC50 = 110 nM).
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Hu, JD
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Cwi, CL
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Cwi, CL
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Smiley, DL
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Smiley, DL
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Timm, D
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Timm, D
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Erickson, JA
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McGee, JE
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McGee, JE
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Yang, HC
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Yang, HC
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Mendel, D
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Mendel, D
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May, PC
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Shapiro, M
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Shapiro, M
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McCarthy, JR
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Hu, JD
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Cwi, CL
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Cwi, CL
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Smiley, DL
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Smiley, DL
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Timm, D
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Timm, D
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Erickson, JA
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Erickson, JA
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McGee, JE
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
McGee, JE
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Yang, HC
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Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
Yang, HC
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Mendel, D
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Mendel, D
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May, PC
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Shapiro, M
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Shapiro, M
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McCarthy, JR
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