Imidazo[1,2-a]pyridine-based HDAC6 Inhibitor a17 for the treatment of Alzheimer’s disease

06/09/2026

AI Summary

a17 is a potent, selective imidazo[1,2-a]pyridine-based HDAC6 inhibitor (IC50 7.51 nM) showing robust neuroprotection in L-Glu/Aβ25-35 HT22 cell models.
a17 demonstrates favourable blood-brain barrier permeability and drug-likeness, enabling in vivo efficacy in zebrafish and mouse models of Alzheimer's pathology.
Treatment with a17 attenuated AD-like phenotypes and memory deficits, likely via differential regulation of ODC1, Serpine1 and PAG-1.

AI Summary

Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive.

In our previous study, a series of novel imidazo[1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects.

Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1.

Basic summary

Eur J Pharmacol. 2026 Sep 5:179320. doi: 10.1016/j.ejphar.2026.179320. Online ahead of print.

ABSTRACT

Alzheimer’s disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo[1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC₅₀ value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ_25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl₃)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.

PMID:42700810 | DOI:10.1016/j.ejphar.2026.179320

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