Novel Nrf2 inducers with multitarget activities for the treatment of neurodegenerative diseases

Résumé

Neurodegenerative diseases (NDDs) are characterized by a progressive loss of neurons in the brain or spinal cord, that lead to a loss of function of the affected areas. The lack of effective treatments, and the ever increasing life expectancy, is raising the number of individuals affected and has a tremendous social and economic impact; therefore, there is an urgent need to find disease-modifying treatments (DMT) for those diseases. Research over the last decades has increased the general knowledge about the underlying pathological mechanisms leading to cell death in NDDs. However, there is an enormous translational gap from basic biology to clinics that hampers the development of new DMTs. Based on the premise that common pathological mechanisms occur in several NDDs leading to neuronal death, we proposed the synthesis of multi-target directed compounds to reduce oxidative stress, neuroinflammation and protein misfolding. The combination of activities would provide neuroprotection, that could favorably modify the outcome of these diseases by preventing cell death and restoring function to damaged neurons, resulting in a DMT. In this work we have selected the Nrf2 ARE pathway that regulates the cellular antioxidant response and the expression of cytoprotective enzymes, as main target to be implemented to the novel compounds. Secondly, we based the design of novel compounds on melatonin, a neurohormone that has antioxidant and neuroprotective activities, and whose levels are highly reduced during aging. Compound ITH12674, a melatonin derivative with Nrf2 inducing activity, has served as a proof-of-concept of the combination of activities proposed. Additionally, two families of compounds were developed based on ITH12674. The pharmacological screening of these families led to the discovery of compound 103 as lead compound; however, the instability of this molecule was a major drawback. Thus, we have developed an optimized compound based on derivative 103, compound 119, with improved stability and a suitable safety profile. The evaluation of compound 119 in an in vivo model of multiple sclerosis indicates that is a potential drug candidate for NDDs.