Structural variation of the 3-acetamido-4,5,6-trihydroxyazepane iminosugar through epimerization and C -alkylation leads to low micromolar HexAB and NagZ inhibitors.

We report the synthesis of seven-membered iminosugars derived from a 3 S -acetamido-4 R ,5 R ,6 S -trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N -acetylhexosaminidases including human O -GlcNAcase (OGA), human lysosomal β-hexosaminidase (HexAB), and Escherichia coli NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and C -alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (L-ido) and at C-5 (D-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.