Abstract
Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
MeSH terms
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Amination
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism*
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Animals
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / metabolism
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Brain / drug effects
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Brain / metabolism
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Enzyme Inhibitors / blood
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Mice
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Molecular Docking Simulation
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Rats
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Structure-Activity Relationship
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Thiazines / blood
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Thiazines / chemistry*
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Thiazines / pharmacology*
Substances
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Amyloid beta-Peptides
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Enzyme Inhibitors
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Thiazines
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human