Detalle de: S4-02-03: TDZDS: Can we target tau, beta-amyloid and neurodegeneration simultaneously?

The interest in Glycogen Synthase Kinase-3 (GSK-3) is focused on the potential of its inhibitors to treat diseases that have significant limitations in their current treatments, like Alzheimer's disease (AD). All evidence point out to a major role for GSK-3 in the initiation of pre-tangle pathology and possibly plaque pathology, the two pathological hallmarks of AD. In summary, inhibition of GSK-3 would be expected to slow down progression neurodegeneration in AD and constitutes an attractive therapeutic target for these conditions. The small heterocyclic thiadiazolidindiones (TDZDs) represent the first non-ATP competitive GSK-3 inhibitors reported to date and have been proposed as new drugs for the effective treatment of neurodegenerative disorders where tau phosphorylation plays a key role. Different transgenic animal models such as the conditional double transgenic Tet/GSK-3 or the APPxPS1 transgenic mice have been used in chronic treatments to show modification in pathological AD hallmarks such tau hypherphosphorylation or amyloid plaque load. Furthermore, two experimental paradigms (ex vivo OGD and kainate excitotoxicity model) were used to assess the neuroprotective properties of TDZDs. The positive effects observed in these studies confirm the potential of TDZDs to be developed as new therapeutic agents for the future treatment of AD. Our most advanced candidate, called NP031112, has started phase I clinical trials to evaluate safety and pharmacokinetics. Up to date more than 70 healthy volunteers (young and elderly) have been treated orally in single and multiple ascending dose studies. The clinical development program is ongoing.