Abstract
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.
MeSH terms
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Amidines / chemical synthesis*
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Amidines / chemistry
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Amidines / pharmacology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / chemistry
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Amyloid Precursor Protein Secretases / genetics
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Aspartic Acid Endopeptidases / genetics
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Cell Line
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Crystallography, X-Ray
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Cytosine / analogs & derivatives*
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Cytosine / chemical synthesis
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Cytosine / chemistry
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Cytosine / pharmacology
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Fluorescence Resonance Energy Transfer
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Humans
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Ligands
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Magnetic Resonance Spectroscopy
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Models, Molecular*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amidines
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Ligands
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Pyrimidines
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isocytosine
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Cytosine
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
Associated data
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PDB/2VA5
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PDB/2VA6
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PDB/2VA7