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

Abstract

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.

The Communication of Hit Quality Using Natural History Visualizations (NHVs)

“…Compound 26 19 has a warning in [tiering], suggesting that the physicochemical properties of this hit may need to be optimized on the way to becoming an effective probe or drug candidate. Compound 25 20 is relatively free of warnings and appears to be an excellent starting point given its [tiering] value.…”

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions

“…The spirocyclobutane 120 was synthesized to access a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor by reacting the spirocyclobutyl bromide 119 with 4-fluorophenylboronic acid under NiI 2 /L11 catalysis, and in the presence of NaHMDS 76 (Scheme 56, eqn (1)). Similar conditions were used to introduce a pyridyl moiety on the spirocyclobutyl iodide 121, however, the reaction had to be performed in iPrOH under microwave irradiation and the yield in 122 was low (9%) 77 (Scheme 56, eqn (2)). The stereocontrol of the construction of a Csp 3 -Csp 3 bond between iodocyclobutane and the racemic β-bromozinc amide 125 was achieved using a nickel catalyst and a chiral ligand, (S)-L12.…”

Advances in Strategies and Tools Available for Interrogation of Protein O‐GlcNAcylation

“…There are increased O‐GlcNAc levels in various cancers, and reduction of OGT expression decreases cancer cell proliferation and metastasis [12,13] . Decreased O‐GlcNAcylation with adversely increased phosphorylation has been associated with neurodegenerative diseases, [14] and pharmacological inhibition of OGA has been shown to reduce some of the pathogenic markers of neurodegenerative diseases [15,16] . Moreover defects in OGT and OGA enzyme genes are potential causes of intellectual disability [17] and type II diabetes, [18] respectively.…”

“…Moreover defects in OGT and OGA enzyme genes are potential causes of intellectual disability [17] and type II diabetes, [18] respectively. Aberrant O‐GlcNAcylation and expression of its regulating enzymes have been associated with cancer, [13] diabetes, [19] and neurological disorders [15,16] . Therefore, OGT and OGA are potential targets of therapeutic interventions.…”