Diazaspirononane Nonsaccharide Inhibitors of O‑GlcNAcase (OGA) for the Treatment of Neurodegenerative Disorders

O-GlcNAcylation
is a post-translational modification of tau understood
to lower the speed and yield of its aggregation, a pathological hallmark
of Alzheimer’s disease (AD). O-GlcNAcase (OGA) is the only
enzyme that removes O-linked N-acetyl-d-glucosamine
(O-GlcNAc) from target proteins. Therefore, inhibition of OGA represents
a potential approach for the treatment of AD by preserving the O-GlcNAcylated
tau protein. Herein, we report the multifactorial optimization of
high-throughput screening hit 8 to a potent, metabolically
stable, and orally bioavailable diazaspirononane OGA inhibitor (+)-56. The human OGA X-ray crystal structure has been recently
solved, but bacterial hydrolases are still widely used as structural
homologues. For the first time, we reveal how a nonsaccharide series
of inhibitors binds bacterial OGA and discuss the suitability of two
different bacterial orthologues as surrogates for human OGA. These
breakthroughs enabled structure–activity relationships to be
understood and provided context and boundaries for the optimization
of druglike properties.