Person:
León Martínez, Rafael

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First Name
Rafael
Last Name
León Martínez
URI
https://hdl.handle.net/20.500.14352/77525
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
Area
Química Orgánica
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End date: 2019 × Subject: 615.31 ×

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    Novel Multitarget Hybrid Compounds for the Treatment of Alzheimer’s Disease
    (Current Topics in Medicinal Chemistry, 2016) Michalska Dziama, Patrycja; Buendia, Izaskun; Almale Del Barrio, Laura; León Martínez, Rafael
    Alzheimer's disease (AD) is the most prevalent among the aging diseases known as neurodegenerative disorders. Drug design programs over the last two decades were mainly based on the cholinergic, the amyloid or the tau hypothesis. However, none of the new drugs have a real impact on the outcome of the disease. The complex nature of AD has led to new approaches for drug development programs, the multitarget drug design hypothesis. Based on this hypothesis, the generation of multitarget hybrid compounds from previously known active molecules has been one of the most widely used to obtain new candidates for the future treatment of AD. Here, we summarize recent developments based on the hybridization hypothesis to obtain a potential clinical candidate for AD.
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    Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases
    (Pharmacology & Therapeutics, 2016) Buendia, Izaskun; Michalska Dziama, Patrycja; Navarro González De Mesa, Elisa; Gameiro, Isabel; Egea, Javier; León Martínez, Rafael
    Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is increasing, the prevalence of these diseases is augmenting exponentially. Despite the great efforts to find a cure, current treatments remain ineffective or have low efficacy. Increasing lines of evidence point to exacerbated oxidative stress, mitochondrial dysfunction and chronic neuroinflammation as common pathological mechanisms underlying neurodegeneration. We will address the role of the nuclear factor E2-related factor 2 (Nrf2) as a potential target for the treatment of NDDs. The Nrf2–ARE pathway is an intrinsic mechanism of defence against oxidative stress. Nrf2 is a transcription factor that induces the expression of a great number of cytoprotective and detoxificant genes. There are many evidences that highlight the protective role of the Nrf2–ARE pathway in neurodegenerative conditions, as it reduces oxidative stress and neuroinflammation. Therefore, the Nrf2 pathway is being increasingly considered a therapeutic target for NDDs. Herein we will review the deregulation of the Nrf2 pathway in different NDDs and the recent studies with Nrf2 inducers as “proof-of-concept” for the treatment of those devastating pathologies.
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    Inclusion complex of ITH12674 with2-hydroxypropyl-beta-cyclodextrin: Preparation, physical characterization and pharmacological effect
    (Carbohydrate Polymers, 2016) Michalska Dziama, Patrycja; Wojnicz, Aneta; Ruiz-Nuño, Ana; Abril, Sheila; Buendia, Izaskun; León Martínez, Rafael
    ITH12674 is a multitarget drug, designed to exert a dual “drug-prodrug” mechanism of action, able toinduce the phase II antioxidant and anti-inflammatory response for the treatment of brain ischemia.However, its physicochemical properties limit its potential preclinical development due to its low watersolubility and instability towards heat and pH variations. In order to improve its properties, we preparedthe inclusion complex of ITH12674 with 2-hydroxypropyl- -cyclodextrin (HP- -CD) by the freeze-drying method. The formation of the inclusion complex was confirmed by FT-IR spectroscopy, PXRD,DSC,1H NMR and SEM techniques. Experimental results showed that the inclusion complex enhanced itswater solubility and stability against heat, acidic and basic conditions. Furthermore, the inclusion com-plex, prepared in water solution, exerted the same potency to induce the phase II antioxidant response asthe pure ITH12674. Thus the formation of the inclusion complex with HP- -CD is a very effective methodto stabilize and solubilize the active compound for its future preclinical development.