Nuevos inductores de NRF2 e inhibidores selectivos de MAO-B para el tratamiento de la enfermedad de Parkinson

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología. Fecha de Lectura: 16-09-2022Esta tesis tiene embargado el acceso al texto completo hasta el 16-03-2024Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Currently, there are only symptomatic treatments available that do not stop the progression of the disease, highlighting the need of innovative therapies. Selective loss of dopaminergic neurons, along with the presence of α-synuclein protein deposits, are considered main events in PD. The development of this neuropathology arises from the complex interaction between different altered molecular pathways such as protein homeostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation, among others. Therefore, the wide spectrum of physiological functions regulated by transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) makes it a promising target for the development of new treatments for complex multifactorial diseases as PD. NRF2 is involved in the control of several cytoprotective genes related, among other processes, to oxidative stress, inflammation and protein homeostasis, which are altered in PD. In this work, we proposed the development of two novel families of NRF2 inducers with complementary activities. These compounds are designed considering melatonin structure as scaffold and, importantly, they include monoamine oxidase B (MAO-B) enzyme selective inhibition, also involved in the control of oxidative stress. It is important to note that MAO-B inhibitors have been used for years in clinics to treat PD symptoms. The first family of 2-(1H-indol-3-yl)ethan-1-amine derivatives showed interesting NRF2 induction and MAO-B potent and selective inhibition, combined with anti-inflammatory, antioxidant and potential blood-brain barrier permeability properties. Furthermore, neuroprotection was observed in oxidative stress-related in vitro models recapitulating some PD features, as well as in a more complex model of adult rat striatal slices. Based on these data, we performed an optimization program in several stages, including a virtual screening approach, to improve the potency and drug-like properties of the novel compounds. Novel N-(1H-indol-5-yl)cinnamamide derivatives exhibited an overall improved pharmacological profile, with increased NRF2 induction potency, MAO-B selectivity, and remarkably better potential blood-brain barrier permeability. They also demonstrated enhanced neuroprotective capacity, with decreased cellular toxicity, maintaining the complementary antioxidant and anti-inflammatory properties observed with the former compounds. Additionally, N-(1H-indol-5-yl)cinnamamide family hit compound was able to reduce α-synuclein levels in dopaminergic cells stably overexpressing this protein, showing a significant activation of proteasomal degradation and macroautophagy lysosomal pathways. In summary, we have developed new series of multitarget melatonin derivatives. We were able to optimize the pharmacological profile of the novel compounds as part of a multi-stage medicinal chemistry program to finally obtain a promising hit compound for the treatment of PDThis work has been developed at Universidad Autónoma de Madrid, Instituto Teófilo Hernando and Neurodegenerative Diseases Institute (IMN, Bordeaux). This research has been possible thanks to the funding support provided by the Ministry of Universities (FPU 16/03977), Instituto de Investigación Sanitaria Carlos III (PI14/00372, PI17/01700) and the Community of Madrid (B2017/BMD-3827