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.

• Authors: Carlos M Martínez-Viturro, Andrés A Trabanco, Jordi Royes, Elena Fernández, Gary Tresadern, Juan A Vega, Alcira Del Cerro, Francisca Delgado, Aránzazu García Molina, Fulgencio Tovar, Paul Shaffer, Andreas Ebneth, Alexis Bretteville, Liesbeth Mertens, Marijke Somers, Jose M Alonso, José M Bartolomé-Nebreda
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 22 Pg. 14017-14044 (11 25 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 33197187 (Publication Type: Journal Article)

Chemical References

• Aza Compounds
• Enzyme Inhibitors
• beta-N-Acetylhexosaminidases

Topics

• Animals
• Aza Compounds (chemistry, pharmacology)
• Catalysis
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Structure
• Mutagenesis
• Neurodegenerative Diseases (drug therapy)
• Structure-Activity Relationship
• beta-N-Acetylhexosaminidases (antagonists & inhibitors, metabolism)