2. Academic Validation
  3. Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies

Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies

  • ACS Med Chem Lett. 2026 Apr 23;17(5):1096-1105. doi: 10.1021/acsmedchemlett.6c00017.
Jakob Bouton 1,  Alexis Bretteville 1,  Gary Tresadern 1,  Paul Shaffer 2,  Nigel Austin 1,  Peter Buijnsters 1,  E Peder Cedervall 1,  Nicolas Darville 1,  Ineke Fonteyn 1,  Joseph Leenaerts 1,  Carolina Martínez Lamenca 1,  Liesbeth Mertens 1,  Daniele Peeters 1,  Adriana I Velter 1,  Yves Van Roosbroeck 1,  Andreas Ebneth 1,  Jose Manuel Bartolomé 3,  Andrés A Trabanco 3,  Daniel Oehlrich 1
Affiliations

Affiliations

  • 1 Johnson & Johnson, Turnhoutseweg 30, Beerse 2340, Belgium.
  • 2 Johnson & Johnson, 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
  • 3 Johnson & Johnson, C/Jarama 75A, 45007 Toledo, Spain.
PMID: 42157845 DOI: 10.1021/acsmedchemlett.6c00017
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular Amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.

Keywords

5-azaindole; Alzheimer’s disease; O-GlcNAcase inhibitors; Structure-based design; Tau pathology.

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