Person:
López-Alvarado Gutiérrez, María Pilar

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First Name
María Pilar
Last Name
López-Alvarado Gutiérrez
URI
https://hdl.handle.net/20.500.14352/77743
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Orgánica
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Author: Arribas Blázquez, Marina × Start date: 2002 ×

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    Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
    (Journal of Medicinal Chemistry, 2022) Martín Cámara, Olmo; Arribas Blázquez, Marina; Wells, Geoffrey; Morales-Tenorio, Marcos; Martin Requero, Ángeles; Porras, Gracia; Martínez, Ana; Giorgi, Giorgo; López-Alvarado Gutiérrez, María Pilar; Lastres Becker, Isabel; Menéndez Ramos, José Carlos
    Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.