New compound as dual inhibitors of GSK3b – AChE and Nrf2 inducers for the treatment of neurodegenerative diseases
Desarrollado por: IIS del Hospital Universitario de La Princesa
Two main disease-mechanism approaches for drug discovery, which have been studied for more than 10 years, are based on the involvement of two proteins: amyloid-β and tau, in AD pathology. However, it has also been suggested that the formation of neurofibrillary tangles, rather than amyloid load, correlates with cognitive impairment, as tau pathology alone has been shown to be sufficient to cause frontotemporal dementia. Tractable targets in the pathway from tau to tangle formation remain to be identified – tau kinases have been proposed as targets. The main kinase proposed to be related with tau hyperphosphorylation is GSK3β. Therefore, by targeting GSK3β the new compounds will reduce tau hyperphosphorylation and tangle formation. Developed compounds were also designed to inhibit acetyl-cholinesterase (AChE) at the peripheral site, which is known to accelerate the formation of amyloid plaques. Recently, new links between oxidative stress and down-regulation of survival pathways have been identified. The advance of AD correlates with the down-regulation of the Nrf2-ARE gene expression pathway. The Nrf2-ARE pathway induces the expression of anti-oxidative stress proteins that are capable of reducing damage in the presence of ROS. Compelling evidence has linked unusual GSK-3β activity with Nrf2-ARE pathway down-regulation.
Therefore, by inhibiting this key kinase it is planned to up-regulate this important AD survival pathway. At the same time, by including specific Nrf2 inducer in the designed molecules, they will potentiate, even more, the Nrf2-ARE antioxidant pathway. This new concept is leading to significant advances in the field of drug rational design and promises many exciting future developments.
On the basis of these observations, we have developed one drug implementing three activities acting, in a complementary manner, on different targets of the apoptotic metabolic crossroads, with synergic neuroprotective effects. Therefore, we have obtained new compounds able to inhibit GSK- 3β, to reduce Aβ aggregation and to induce the Nrf2-ARE pathway to obtain a disease-modifying drug. The induction of Nrf2 has also implemented anti-inflammatory activity, demonstrated in primary glial cultures, as they are able to reduce the production of nitrites upon stimulation with lipopolysaccharide
Due to the key role of both enzymes GSK3β and AChE, oxidative stress and neuroinflammation in the development of AD pathology, these compounds have been designed specifically to target several pathological pathways. These compounds were designed as potential treatments for Alzheimer’s diseasends are dual inhibitors of GSK3β and AChE, moderate Nrf2 inducers, anti-inflammatory and neuroprotectants in several oxidative stress models related to Alzheimer’s disease.
Estado de protección
Cooperación que se desea
Our interest of collaboration with pharmaceutical industry is to further develop this family of compounds. First, to perform the in vivo proof of concept of the lead compound and, second to optimize the activities to generate a drug candidate. We also are looking for biopharmaceutical companies interested in licensing the compounds or collaborating to apply for funding to the European Commision. Thus, we are open to make collaboration with companies interested in granting our project.