AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans

Abstract

Abnormal tau phosphorylation resulting in detachment of tau from microtubules and aggregation are critical events in neuronal dysfunction, degeneration, and neurofibrillary pathology seen in Alzheimer's disease. Glycogen synthase kinase3b (GSK3b) is a key target for drug discovery in the treatment of Alzheimer's disease and related tauopathies because of its potential to abnormally phosphorylate proteins and contribute to synaptic degeneration. We report the discovery of AZD1080, a potent and selective GSK3 inhibitor that demonstrates peripheral target engagement in Phase 1 clinical studies. AZD1080 inhibits tau phosphorylation in cells expressing human tau and in intact rat brain. Interestingly, subchronic but not acute administration with AZD1080 reverses MK-801-induced deficits, measured by long-term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3b signaling. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Consistent with the preclinical data, in multiple ascending dose studies in healthy volunteers, a prolonged suppression of glycogen synthase activity was observed in blood mononuclear cells providing evidence of peripheral target engagement with a selective GSK3 inhibitor in humans.

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…Moreover, potent GSK-3 inhibition can lead to toxicity (as occurs with lithium treatment in the brain, causing motor deficits 104 ), so care must be taken to only mildly inhibit the enzyme. AZD1080, a GSK-3 inhibitor from AstraZeneca, exhibited some success in limited phase I clinical trials for Alzheimer’s disease, but blood glucose was not measured 105 . Another GSK-3 inhibitor, tideglusib (Noscria), was used in a phase II clinical trial for progressive supranuclear palsy 106 .…”

Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors to activate Wnt/β-catenin pathway

“…In consistent with this homology, many GSK-3b inhibitors are also potent inhibitors of CDKs [22][23][24][25]. Selectivity is thus considered as a major issue to develop potent GSK-3b inhibitors as probes for biological functions of GSK-3b and drugs for the treatment of various diseases [18,[26][27][28][29][30][31].…”

Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials

“…Indeed, several compounds have been developed to inhibit GSK-3 activity, such as tideglusib and AZD1080. However, the former completed a phase II study without demonstrating significant clinical improvements in subjects with AD, whereas AZD1080 has completed a phase I trial with a confirmed target engagement and good safety and tolerability profiles [23].…”