Abstract
Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Catalysis
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Chemistry Techniques, Synthetic
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Copper / chemistry
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / chemistry
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Humans
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Molecular Structure
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Thiadiazines / chemical synthesis*
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Thiadiazines / chemistry
Substances
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Cyclic S-Oxides
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Thiadiazines
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Copper
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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verubecestat