2. Academic Validation
  3. Network-Based Drug Optimization toward the Treatment of Parkinson's Disease: NRF2, MAO-B, Oxidative Stress, and Chronic Neuroinflammation

Network-Based Drug Optimization toward the Treatment of Parkinson's Disease: NRF2, MAO-B, Oxidative Stress, and Chronic Neuroinflammation

  • J Med Chem. 2025 Feb 13;68(3):3495-3517. doi: 10.1021/acs.jmedchem.4c02659.
Pablo Duarte 1,  Francisco J Sanchez-Porro 1,  Enrique Crisman 1 2,  Ángel Cores 3,  Irene Jiménez 1 2,  Antonio Cuadrado 4 5,  J Carlos Menéndez 3,  Rafael León 1
Affiliations

Affiliations

  • 1 Consejo Superior de Investigaciones Científicas (IQM-CSIC), Instituto de Química Médica, 28006 Madrid, Spain.
  • 2 Fundación Teófilo Hernando para la I+D del Medicamento, Las Rozas, 28290 Madrid, Spain.
  • 3 Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
  • 4 Instituto de Investigación Sanitaria La Paz (IdiPaz) and Departamento de Bioquímica, Facultad de Medicina, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, 28029 Madrid, Spain.
  • 5 Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain.
PMID: 39818855 DOI: 10.1021/acs.jmedchem.4c02659
Abstract

Parkinson's disease (PD), the second most common neurodegenerative disorder, affects around 10 million people worldwide. It is a multifactorial disease marked by dopaminergic neuron loss with oxidative stress (OS) and neuroinflammation as key pathological drivers. Current treatments focus on dopamine replacement and are symptomatic, underscoring the urgent need for disease-modifying therapies. Here, we present a novel class of dual MAO-B inhibitors and NRF2 inducers with neuroprotective properties in in vitro PD models. Through an optimization program, we enhanced their MAO-B inhibitory potency, selectivity, and NRF2 induction capacity while achieving favorable pharmacokinetic profiles. Virtual library screening identified two core derivatives, leading to the development of compound 11, which exhibited potent anti-inflammatory and neuroprotective activity in OS-related in vitro models. Compound 11 also demonstrated high liver microsomal stability and favorable pharmacokinetics in mice, making it a promising candidate for further investigation as a potential PD therapy.

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