New inhibitors of the ß-site amyloid precursor protein cleaving enzyme (BACE-1) are described. The hydroxyethyl transition state isostere of GT1017 has been replaced by the hydroxyethylamine (HEA), the hydroxyethylsulfide or the hydroxyethylurea groups. Biological evaluation has shown that the HEA analogue, obtained as epimeric mixture, inhibited BACE-1 with an IC50=0.12μM. Stereoselective synthesis showed surprisingly that the most active stereoisomer was the (R)-HEA transition state analogue with an IC50=0.014μM.
Keywords: bace-1, secretase, memapsin-2, inhibition, transition state analogues, pseudopeptides
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