Abstract
A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Guanidines / chemical synthesis*
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Guanidines / pharmacology*
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Indicators and Reagents
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Models, Molecular
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Pyrroles / chemistry
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / pharmacology*
Substances
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Enzyme Inhibitors
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Guanidines
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Indicators and Reagents
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Pyrroles
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Thiophenes
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human