Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core

We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2′–P3′ position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1′-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 value of 3.1 nM.

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