NeuroDrugs

The research activity of the NeuroDrugs Group at the Medicinal Chemistry Institute is focused on the design, synthesis, biological study, and further optimization of structurally diverse chemical entities for treating neurological diseases. We are especially interested in developing innovative neurogenic and photoswitchable neurodrugs, in the fields of the Regenerative Medicine and the Photopharmacology, respectively.

Regenerative Medicine is one of the most innovative therapeutic approaches for the treatment of different pathologies. Undoubtedly, it will be a mainstay of the future medicine, although nowadays there are still several obstacles to overcome, such as the development of therapies for the nervous system. Efficient regeneration of damaged tissues by an accident (e.g., trauma, stroke), by neurodegenerative diseases (e.g., Alzheimer, Parkinson, amyotrophic lateral sclerosis) or psychiatric conditions (e.g., mood disorders, anxiety, major depression) would be a great advance to achieve the definitive cure for these diseases. Indeed, the discovery of the existence of neural stem-cells niches in the adult human brain opens the door to the development of small molecules as restorative therapies for such pathologies. Our group is interested in contributing to the Regenerative Medicine by the discovery of new drugs able to promote neuro-regeneration by endogenous stimulation of the brain neurogenesis.

Targets involved in neurogenesis are huge and most of them remain to be determined. For this reason, we have focused initially our projects and resources on several targets with different degree of knowledge about their involvement in neuronal plasticity. We have chosen receptors of melatonin, serotonin, cannabinoids, and nicotine, as well as the Wnt/beta-catenin and the nuclear erythroid 2-related factor-antioxidant response elements (Nrf2-ARE) pathways as potential neurogenic targets. All of these pharmacological receptors are involved in the pathology of neurodegenerative and mental diseases and some of them may exert neuroprotective actions through antioxidant, anti-inflammatory and anti-excitotoxicity properties.

Photopharmacology has grown impressively in the last decade and recent findings in areas as diverse as chemistry, biology and pharmacy continue to provide new evidence of their therapeutic potential. Photopharmacology is based in the use of drugs that can be selectively activated and deactivated with irradiation of light at different wavelengths. The use of light provides a fine adjustment in the control of the administration of these drugs, with high spatial and temporal resolution. Photo-activation/deactivation can be achieved inside the organism by activated fluorescent compounds, or from the outside using minimally invasive optical fibres for the delivery of photon excitation in specific tissues. Therefore, the photo-switchable drugs that can be activated and deactivated by their interaction with light may avoid systemic side effects, commonly associated to conventional drugs.

Our group is now involved in developing photoswitchable drugs acting on different types of ion channels, such as nicotinic acetylcholine receptors (nAChR) and voltage-gated potassium-selective (K_v) channels.

RESEARCH LINES

Virtual screening aimed at new therapeutic targets against neurodegenerative diseases.

New drugs against COVID-19: Screening of the group's libraries on a detection platform against SARS-CoV-2 and subsequent optimization by computer-aided rational design.

Rational design, synthesis, pharmacological evaluation and further optimization of innovative drugs for neurological diseases. We use computer-aided rational design to guide the generation of new families of multifunctional drugs capable of acting on different pharmacological targets (melatonin, serotonin, nicotine, and cannabinoid receptors, BACE-1, GSK-3beta, Nrf2, etc.)

Creation and screening of an in-house chemical library composed of about 1000 products with privileged structures to act in the nervous system. As a result of ongoing work on neurodegenerative disease projects, the group has created a computerized collection of compounds with privileged structures to act in the nervous system and which has already produced very positive results. After a screening campaign in oxidative stress cell models, two families of multifunctional mitochondrial neuroprotective drugs have been developed, which were first patented and then published in renowned scientific journals.

Development of biological and pharmacological tools of special interest to our research lines, as in vitro / in silico methods to evaluate biological and drug-like properties (e.g., oral absorption and CNS penetration). Moreover, we develop fluorescent probes for labelling membrane receptors.

FUNDED PROJECTS (2015-now)

Bench to bedside transition for pharmacological regulation of NRF2 in non-communicable diseases (Acronym: BenBedPhar) (COST Action, OC-2020-1-24760, Code: CA20121 https://www.cost.eu/actions/CA20121/). Funding entity: European Cooperation in Science & Technology (COST). Lifetime: ca. 19/10/2021 – 18/10/2025. Coord: A. Cuadrado (UAM), IQM-group Responsibles: M.I. Rodríguez Franco and R. León.

Antivirales, generación de diversidad química. Plataforma de Salud Global. PTI+ Salud Global CSIC SGL2103050. Lifetime: 1/01/2021 – 31/12/2022. IQM-group Responsibles: J.A. Páez and M.I. Rodríguez Franco.

Modulación del receptor cannabinoide CB2 como nueva estrategia terapéutica para proteger contra la neurodegeneración inducida por TAU. Funding Entity: Fundación Tatiana Pérez de Guzmán el Bueno. Lifetime: 1/01/2021-31/12/2024. PI: Isabel Lastres-Becker, IQM-group: J. A. Páez

Novel trifunctional multitarget compounds for the treatment of Alzheimer’s disease, Nrf2 phase II antioxidant response, cholinergic neurotransmission and chronic neuroinflammation (PI20/00433). Funding entity: Instituto de Salud Carlos III. Lifetime: 1/01/2021 – 30/06/2021. IP: R. León.

Investigación traslacional sobre la regulación farmacológica de NRF2 en enfermedades no transmisibles (RED2018-102362-T). Funding entity: Ministerio de Ciencia, Innovación y Universidades (Acciones de dinamización «Redes de Investigación»). Lifetime: 1/01/2020 – 30/06/2022. Coord: A. Cuadrado (UAM), IQM-group Responsible: M.I. Rodríguez Franco.

Modulación del envejecimiento y la neurodegeneración por moléculas pequeñas inhibidoras de proteína quinasas (PID2019-105600RB-I00). Funding entity: MINECO, RETOS Program. Lifetime: 01/06/2020 – 01/06/2023. PI 1: Dr. Ana Martínez (CIB); IP 2 Isabel Lastres (IIB); IQM participant: Dr. Concepción Pérez.

Innovative neurogenic and photoswitchable compounds for the treatment of neurological diseases. From hit to lead guided by an omic-platform for safety and mechanisms of action (NeuPhoDrugs) (RTI2018-093955-B-C21). Funding entity: Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades y Fondos FEDER. Lifetime: 1/01/2019 – 30/09/2022. IP: M.I. Rodríguez Franco.

Combinación de estrategias computacionales, biológicas y sintéticas con aplicación al desarrollo de fármacos (RTI2018-096100B-100). Funding Entity: Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades y Fondos FEDER. Lifetime: 1/01/2019-30/6/2022. PI: Dra. Nuria E. Campillo (CIB), CoPI : J. A. Páez (IQM).

Development of NRF2 activating drugs for innovative therapies of Alzheimer’s disease (S2017/BMD-3827, NRF24AD-CM). Funding entity: Dirección General de Investigación – Comunidad de Madrid. Lifetime: 1/01/2018 – 30/06/2022. Coord: M. G. López (UAM), IQM-group Responsible: M.I. Rodríguez Franco.

Desarrollo preclínico del derivado ITH13001 para el tratamiento oral de nueva generación de la esclerosis múltiple (ACI-FIPSE2018). Funding entity: FIPSE-Instituto de Salud Carlos III. Lifetime: 1/02/2018 – 30/01/2019. IP: R. León.

Vía Nrf2-ARE como base para el diseño de fármacos multidiana frente a rutas patológicas comunes para el tratamiento de enfermedades neurodegenerativas (PI17/01700). Funding entity: Instituto de Salud Carlos III. Lifetime: 1/01/2018 – 31/12/2020. IP: R. León.

Multitarget-designed small molecules targeting protein kinase and BACE1: A new approach for prevention and treatment of cognitive disorders (SAF2016-76693-R) MINECO Biomedicina. Lifetime: 1/01/2017 – 31/12/2019. PI: Dr. Ana Martínez Gil (CIB); IQM participant: Dr. Concepción Pérez.

Preclinical development of ITH13001 as second-generation oral treatment for multiple sclerosis (CI17-00048). Funding entity: CAIXAIMPULSE. Fundación la Caixa – Caixa Capital Risk. Lifetime: 1/07/2017– 31/12/2018. IP: R. León.

Innovative drugs for neurodegenerative diseases (Alzheimer and amyotrophic lateral sclerosis) acting at neurogenic and multifunctional neuroprotective targets (SAF2015-64948-C2-1-R). Funding entity: MINECO Biomedicina. Lifetime: 1/01/2016 – 31/12/2019. PI: M.I. Rodríguez Franco.

Quimio-computación en el descrubrimiento de fármacos multidiana para el tratamiento de la enfermedad de Alzheimer (CTQ2015-66313-R). Funding Entity: MINECO-Plan Nacional. Lifetime: 31/01/2016-31/12/2018. PI: Dra. Nuria E. Campillo (CIB). IQM-group Responsible: J. A. Páez.

Desarrollo de un fármaco innovador para la enfermedad de Parkinson. Seguridad clínica y nuevas terapias con S14 (RTC-2015-3439-1). Funding Entity: MINECO Programa Retos-Colaboración. Lifetime: 1/02/2016-31/12/2018. Coord: Dr. Manuel Sarasa. CSIC-PI: Dra. A. Martínez. IQM-group Responsible: J. A. Páez.

Desarrollo preclínico del derivado ITH13001 para el tratamiento oral de nueva generación de la esclerosis múltiple (FIPSE2016). Funding entity: FIPSE- Instituto de Salud Carlos III. Lifetime: 1/02/2016 – 30/09/2016. IP: R. León.

Hybrid and multitarget compounds for the treatment of retinal neurodegenerative diseases (2015-03-1282). Funding entity: Bayer Pharma A.G. “From targets to novel drugs”. Lifetime: 1/01/2015 – 31/12/2017. Coord: N. Cuenca. IQM responsible: R. León.

Compuestos multidiana quirales para el tratamiento de enfermedades neurodegenerativas: ligandos de receptores nicotínicos, inductores de Nrf2 y anti-inflamatorios (PI14/00372). Funding entity: Instituto de Salud Carlos III. Lifetime: 1/01/2015 – 31/12/2017. IP: R. León.

New mitochondrial protective drugs for the potential treatment of stroke and neurodegenerative diseases such as Alzheimer’s (SAF2012-31035). Funding entity: MINECO Biomedicina. Lifetime: 1/01/2013 – 31/12/2016. PI: M.I. Rodríguez Franco.

Inhibidores de quinasas efectivos para la esclerosis lateral amiotrófica (SAF2012-37979-C03-01). Funding entity: MINECO Biomedicina. Lifetime: 01/01/2013- 31/12/2016. PI: Dr. Ana Martínez Gil (CIB); IQM participant: Dr. Concepción Pérez.

Non-conventional target approach for drug discovery against neurodegenerative diseases: Nrf2 upregulation (FP7-People-2012-CIG-322156). Funding entity: European Commission; Marie Curie Career Integration Grant (CIG). Lifetime: 1/10/2012 – 30/09/2016. IP: R. León.

BOOK CHAPTERS

Ledesma, M.D.; Bortolozzi, A.; Lucas, J.; Barco, A.; Pérez Otaño, I.; Perea, G.; Álvarez Dolado, M.; Adell, A.; López Giménez, J.; Rodríguez-Franco, M. I.; Huertas, R.; Crespo Facorro, B.; Vieta, E. Understanding Mental Disorders. In Brain, Mind & Behaviour. CSIC Scientific Challenges.; 2021; Vol. 5, pp 89–95.

Duarte, P.; Cuadrado, A.; León, R. Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches. In Reactive Oxygen Species Network Pharmacology and Therapeutic Applications; 2021; pp 229–259. https://doi.org/10.1007/164_2020_384.

SELECTED PUBLICATIONS

2022

Codony, S.; Entrena, J.M.; Calvó-Tusell, C.; Jora, B.; González-Cano, R.; Osuna, S.; Corpas, R.; Morisseau, C.; Pérez, B.; Barniol-Xicota, M.; Griñán-Ferré, C.; Pérez, C.; Rodríguez-Franco, M.I.; Martínez, A.L.; Loza, M.I.; Pallàs, M.; Verhelst, S.H.L.; Sanfeliu, C.; Feixas, F.; Hammock, B.D.; Brea, J.; Cobos, E.J.; Vázquez, S. Synthesis, in vitro profiling and in vivo evaluation of benzohomoadamantane-based ureas for visceral pain: a new indication for soluble epoxide hydrolase inhibitors. J. Med. Chem. 2022, 000 (https://doi.org/10.1021/acs.jmedchem.2c00515).

Crisman, E.; Duarte, P.; Dauden, E.; Cuadrado, A.; Rodríguez-Franco, M. I.; López, M. G.; León, R. KEAP1-NRF2 protein-protein interaction inhibitors: design, pharmacological properties and therapeutic potential. Res. Rev. 2022, 000 (http://doi.org/10.1002/med.21925).

Fernández-Ginés, R.; Encinar, J.A.; Hayes, J.D.; Oliva, B.; Estrada-Valencia, M.; Rodríguez-Franco, M.I.; Rojo, A.I.; Cuadrado, A. An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver. Redox Biol. 2022, 55, 102396 (https://doi.org/10.1016/j.redox.2022.102396).

García, M. M.; Molina-Álvarez, M.; Rodríguez-Rivera, C.; Paniagua, N.; Quesada, E.; Uranga, J. A.; Rodríguez-Franco, M. I.; Pascual, D.; Goicoechea, C. Antinociceptive and modulatory effect of pathoplastic changes in spinal glia of a TLR4 /CD14 blocking molecule in two models of pain in rat. Biomed. Pharmacother. 2022, 150, 112986 (10.1016/j.biopha.2022.112986).

Herrera-Arozamena, C.; Estrada-Valencia, M.; López-Caballero, P.; Pérez, C.; Morales-García, J.; Pérez-Castillo, A.; del Sastre, E.; Fernández-Mendívil, C.; Duarte, P.; Michalska, P.; Lombardía, J.; Senar, S.; León, R.; López, M.G.; Rodríguez-Franco, M. I. Resveratrol-based MTDLs to stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades. J. Med. Chem. 2022, 000 (Online ahead of print: March 4, 2022) https://doi.org/10.1021/acs.jmedchem.1c01883.

Duarte, P.; Michalska, P.; Crisman, E.; Cuadrado, A.; León, R. Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disease. Antioxidants 2022, 11 (2), 247. https://doi.org/10.3390/antiox11020247.

Cores, Á.; Michalska, P.; Pérez, J. M.; Crisman, E.; Gómez, C.; Villacampa, M.; Menéndez, J. C.; León, R. Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease. Antioxidants 2022, 11 (1), 112. https://doi.org/10.3390/antiox11010112.

Cores, Á.; Carmona-Zafra, N.; Martín-Cámara, O.; Sánchez, J. D.; Duarte, P.; Villacampa, M.; Bermejo-Bescós, P.; Martín-Aragón, S.; León, R.; Menéndez, J. C. Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants 2021, 11 (1), 28. https://doi.org/10.3390/antiox11010028.

2021

Codony, S.; Calvó-Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M. I.; Brea, J.; Pérez, C.; Rodríguez-Franco, M. I.; Pizarro-Delgado, J.; Corpas, R.; Griñán-Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez-Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis. J. Med. Chem. 2021, 64 (9), 5429–5446. https://doi.org/10.1021/acs.jmedchem.0c01601.

This work received the 2021 Prize for the Best Publication, granted by the Spanish Society of Therapeutic Chemistry (SEQT).

Delogu, G. L.; Kumar, A.; Gatto, G.; Bustelo, F.; Saavedra, L. M.; Rodríguez-Franco, M. I.; Laguna, R.; Viña, D. Synthesis and in Vitro Study of Nitro- and Methoxy-2-Phenylbenzofurans as Human Monoamine Oxidase Inhibitors. Bioorg. Chem. 2021, 104616. https://doi.org/10.1016/j.bioorg.2020.104616.

Nozal, V.; García‐Rubia, A.; Cuevas, E. P.; Pérez, C.; Tosat‐Bitrián, C.; Bartolomé, F.; Carro, E.; Ramírez, D.; Palomo, V.; Martínez, A. From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer’s Disease Using Protein‐Templated Synthesis. Angew. Chem. Int. Ed. 2021, 60 (35), 19344–19354. https://doi.org/10.1002/anie.202106295.

Cores, Á.; Abril, S.; Michalska, P.; Duarte, P.; Olives, A. I.; Martín, M. A.; Villacampa, M.; León, R.; Menéndez, J. C. Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation. Antioxidants 2021, 10 (6), 941. https://doi.org/10.3390/antiox10060941.

Grieco, I.; Bissaro, M.; Tiz, D. B.; Perez, D. I.; Perez, C.; Martinez, A.; Redenti, S.; Mariotto, E.; Bortolozzi, R.; Viola, G.; Cozza, G.; Spalluto, G.; Moro, S.; Federico, S. Developing Novel Classes of Protein Kinase CK1δ Inhibitors by Fusing [1,2,4]Triazole with Different Bicyclic Heteroaromatic Systems. Eur. J. Med. Chem. 2021, 216, 113331. https://doi.org/10.1016/j.ejmech.2021.113331.

Rojas-Prats, E.; Martinez-Gonzalez, L.; Gonzalo-Consuegra, C.; Liachko, N. F.; Perez, C.; Ramírez, D.; Kraemer, B. C.; Martin-Requero, Á.; Perez, D. I.; Gil, C.; de Lago, E.; Martinez, A. Targeting Nuclear Protein TDP-43 by Cell Division Cycle Kinase 7 Inhibitors: A New Therapeutic Approach for Amyotrophic Lateral Sclerosis. Eur. J. Med. Chem. 2021, 210. https://doi.org/10.1016/j.ejmech.2020.112968.

Davies, M. P.; Benitez, R.; Perez, C.; Jakupovic, S.; Welsby, P.; Rzepecka, K.; Alder, J.; Davidson, C.; Martinez, A.; Hayes, J. M. Structure-Based Design of Potent Selective Nanomolar Type-II Inhibitors of Glycogen Synthase Kinase-3β. J. Med. Chem. 2021, 64 (3), 1497–1509. https://doi.org/10.1021/acs.jmedchem.0c01568.

González-Ruiz, V.; Cores, Á.; Martín-Cámara, O.; Orellana, K.; Cervera-Carrascón, V.; Michalska, P.; Olives, A. I.; León, R.; Martín, M. A.; Menéndez, J. C. Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation. Pharmaceutics 2021, 13 (10), 1609. https://doi.org/10.3390/pharmaceutics13101609.

Gürbüz, P.; Dokumacı, A. H.; Gündüz, M. G.; Perez, C.; Göger, F.; Paksoy, M. Y.; Yerer, M. B.; Ömür Demirezer, L. In Vitro Biological Activity of Salvia Fruticosa Mill. Infusion against Amyloid β-Peptide-Induced Toxicity and Inhibition of GSK-3β, CK-1δ, and BACE-1 Enzymes Relevant to Alzheimer’s Disease. Saudi Pharm. J. 2021, 29 (3), 236–243. https://doi.org/10.1016/j.jsps.2021.01.007

2020

Herrera-Arozamena, C.; Estrada-Valencia, M.; Martí-Marí, O.; Pérez, C.; de la Fuente Revenga, M.; Villalba-Galea, C. A.; Rodríguez-Franco, M. I. Optical Control of Muscular Nicotinic Channels with Azocuroniums, Photoswitchable Azobenzenes Bearing Two N-Methyl-N-Carbocyclic Quaternary Ammonium Groups. Eur. J. Med. Chem. 2020, 200, 112403. https://doi.org/10.1016/j.ejmech.2020.112403.

Herrera-Arozamena, C.; Estrada-Valencia, M.; Pérez, C.; Lagartera, L.; Morales-García, J. A.; Pérez-Castillo, A.; Franco-Gonzalez, J. F.; Michalska, P.; Duarte, P.; León, R.; López, M. G.; Mills, A.; Gago, F.; García-Yagüe, Á. J.; Fernández-Ginés, R.; Cuadrado, A.; Rodríguez-Franco, M. I. Tuning Melatonin Receptor Subtype Selectivity in Oxadiazolone-Based Analogues: Discovery of QR2 Ligands and NRF2 Activators with Neurogenic Properties. Eur. J. Med. Chem. 2020, 190, 112090. https://doi.org/10.1016/j.ejmech.2020.112090.

Codony, S.; Pujol, E.; Pizarro, J.; Feixas, F.; Valverde, E.; Loza, M. I.; Brea, J. M.; Saez, E.; Oyarzabal, J.; Pineda-Lucena, A.; Pérez, B.; Pérez, C.; Rodríguez-Franco, M. I.; Leiva, R.; Osuna, S.; Morisseau, C.; Hammock, B. D.; Vázquez-Carrera, M.; Vázquez, S. 2-Oxaadamant-1-Yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis. J. Med. Chem. 2020, 63 (17), 9237–9257. https://doi.org/10.1021/acs.jmedchem.0c00310.

Michalska, P.; Mayo, P.; Fernández-Mendívil, C.; Tenti, G.; Duarte, P.; Buendia, I.; Ramos, M. T.; López, M. G.; Menéndez, J. C.; León, R. Antioxidant, Anti-Inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease. Antioxidants 2020, 9 (8), 650. https://doi.org/10.3390/antiox9080650.

Michalska, P.; Tenti, G.; Satriani, M.; Cores, A.; Ramos, M. T.; García, A. G.; Menéndez, J. C.; León, R. Aza‐CGP37157‐lipoic Hybrids Designed as Novel Nrf2‐inducers and Antioxidants Exert Neuroprotection against Oxidative Stress and Show Neuroinflammation Inhibitory Properties. Drug Dev. Res. 2020, 81 (3), 283–294. https://doi.org/10.1002/ddr.21618.

Espadinha, M.; Viejo, L.; Lopes, R. M. R. M.; Herrera-Arozamena, C.; Molins, E.; dos Santos, D. J. V. A.; Gonçalves, L.; Rodríguez-Franco, M. I.; Ríos, C. de los; Santos, M. M. M. Identification of Tetracyclic Lactams as NMDA Receptor Antagonists with Potential Application in Neurological Disorders. Eur. J. Med. Chem. 2020, 194, 112242. https://doi.org/10.1016/j.ejmech.2020.112242.

Michalska, P.; Buendia, I.; Duarte, P.; FernandezMendivil, C.; Negredo, P.; Cuadrado, A.; López, M. G.; Leon, R. Melatonin-Sulforaphane Hybrid ITH12674 Attenuates Glial Response in Vivo by Blocking LPS Binding to MD2 and Receptor Oligomerization. Pharmacol. Res. 2020, 152, 104597. https://doi.org/10.1016/j.phrs.2019.104597.

González-Naranjo, P.; Pérez, C.; Girón, R.; Sánchez-Robles, E. M.; Martín-Fontelles, M. I.; Carrillo-López, N.; Martín-Vírgala, J.; Naves, M.; Campillo, N. E.; Páez, J. A. New Cannabinoid Receptor Antagonists as Pharmacological Tool. Bioorg. Med. Chem. 2020, 28 (19), 115672. https://doi.org/10.1016/j.bmc.2020.115672.

Campello, L.; Kutsyr, O.; Noailles, A.; Michalska, P.; Fernández-Sánchez, L.; Martínez-Gil, N.; Ortuño-Lizarán, I.; Sánchez-Sáez, X.; de Juan, E.; Lax, P.; León, R.; García, A. G.; Cuenca, N.; Maneu, V. New Nrf2-Inducer Compound ITH12674 Slows the Progression of Retinitis Pigmentosa in the Mouse Model Rd10. Cell. Physiol. Biochem. 2020, 54 (1), 142–159. https://doi.org/10.33594/000000210.

Di Martino, R. M. C.; Pruccoli, L.; Bisi, A.; Gobbi, S.; Rampa, A.; Martinez, A.; Pérez, C.; Martinez-Gonzalez, L.; Paglione, M.; Di Schiavi, E.; Seghetti, F.; Tarozzi, A.; Belluti, F. Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3β Inhibitor/Nrf2 Inducer for the Treatment of Parkinson’s Disease. ACS Chem. Neurosci. 2020, 11 (17), 2728–2740. https://doi.org/10.1021/acschemneuro.0c00363.

Cores, Á.; Piquero, M.; Villacampa, M.; León, R.; Menéndez, J. C. NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases. Biomolecules 2020, 10 (6), 904. https://doi.org/10.3390/biom10060904.

Nuñez-Borque, E.; González-Naranjo, P.; Bartolomé, F.; Alquézar, C.; Reinares-Sebastián, A.; Pérez, C.; Ceballos, M. L.; Páez, J. A.; Campillo, N. E.; Martín-Requero, Á. Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer’s Disease Lymphoblast Alterations. Mol. Neurobiol. 2020, 57 (4), 1938–1951. https://doi.org/10.1007/s12035-019-01813-4.

Michalska, P.; León, R. When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration. Antioxidants 2020, 9 (8), 740. https://doi.org/10.3390/antiox9080740.

Lassagne, F.; Duguépéroux, C.; Roca, C.; Perez, C.; Martinez, A.; Baratte, B.; Robert, T.; Ruchaud, S.; Bach, S.; Erb, W.; Roisnel, T.; Mongin, F. From Simple Quinoxalines to Potent Oxazolo[5,4- f ]Quinoxaline Inhibitors of Glycogen-Synthase Kinase 3 (GSK3). Org. Biomol. Chem. 2020, 18 (1), 154–162. https://doi.org/10.1039/C9OB02002K.

2019

Estrada-Valencia, M.; Herrera-Arozamena, C.; Pérez, C.; Viña, D.; Morales-García, J. A.; Pérez-Castillo, A.; Ramos, E.; Romero, A.; Laurini, E.; Pricl, S.; Rodríguez-Franco, M. I. New Flavonoid – N,N-Dibenzyl(N-Methyl)Amine Hybrids: Multi-Target-Directed Agents for Alzheimer´s Disease Endowed with Neurogenic Properties. J. Enzyme Inhib. Med. Chem. 2019, 34 (1), 712–727. https://doi.org/10.1080/14756366.2019.1581184.

González-Naranjo, P.; Pérez-Macias, N.; Pérez, C.; Roca, C.; Vaca, G.; Girón, R.; Sánchez-Robles, E.; Martín-Fontelles, M. I.; de Ceballos, M. L.; Martin-Requero, A.; Campillo, N. E.; Páez, J. A. Indazolylketones as New Multitarget Cannabinoid Drugs. Eur. J. Med. Chem. 2019, 166, 90–107. https://doi.org/10.1016/j.ejmech.2019.01.030.

Gürbüz, P.; Martinez, A.; Pérez, C.; Martínez-González, L.; Göger, F.; Ayran, İ. Potential Anti-Alzheimer Effects of Selected Lamiaceae Plants through Polypharmacology on Glycogen Synthase Kinase-3β, β-Secretase, and Casein Kinase 1δ. Ind. Crops Prod. 2019, 138, 111431. https://doi.org/10.1016/j.indcrop.2019.05.080.

Herrera-Arozamena, C.; Estrada-Valencia, M. H.; Villalba-Galea, C. A.; Rodriguez-Franco, M. I. Structure-Activity Relationship of Potent Photo-Switchable Neuromuscular Inhibitors. Biophys. J. 2019, 116 (3), 395a. https://doi.org/10.1016/j.bpj.2018.11.2134.

Luengo, E.; Buendia, I.; Fernández‐Mendívil, C.; Trigo‐Alonso, P.; Negredo, P.; Michalska, P.; Hernández‐García, B.; Sánchez‐Ramos, C.; Bernal, J. A.; Ikezu, T.; León, R.; López, M. G. Pharmacological Doses of Melatonin Impede Cognitive Decline in Tau‐related Alzheimer Models, Once Tauopathy Is Initiated, by Restoring the Autophagic Flux. J. Pineal Res. 2019, e12578. https://doi.org/10.1111/jpi.12578.

Páez, J. A.; Campillo, N. E. Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases. Curr. Med. Chem. 2019, 26 (18), 3300–3340. https://doi.org/10.2174/0929867325666180226095132.

Ponzoni, I.; Sebastián-Pérez, V.; Martínez, M. J.; Roca, C.; De la Cruz Pérez, C.; Cravero, F.; Vazquez, G. E.; Páez, J. A.; Díaz, M. F.; Campillo, N. E. QSAR Classification Models for Predicting the Activity of Inhibitors of Beta-Secretase (BACE1) Associated with Alzheimer’s Disease. Sci. Rep. 2019, 9 (1), 9102. https://doi.org/10.1038/s41598-019-45522-3.

Redenti, S.; Marcovich, I.; De Vita, T.; Pérez, C.; De Zorzi, R.; Demitri, N.; Perez, D. I.; Bottegoni, G.; Bisignano, P.; Bissaro, M.; Moro, S.; Martinez, A.; Storici, P.; Spalluto, G.; Cavalli, A.; Federico, S. A Triazolotriazine‐Based Dual GSK‐3β/CK‐1δ Ligand as a Potential Neuroprotective Agent Presenting Two Different Mechanisms of Enzymatic Inhibition. ChemMedChem 2019, 14 (3), 310–314. https://doi.org/10.1002/cmdc.201800778.

Rubio-Navarro, A.; Vázquez-Carballo, C.; Guerrero-Hue, M.; García-Caballero, C.; Herencia, C.; Gutiérrez, E.; Yuste, C.; Sevillano, Á.; Praga, M.; Egea, J.; Cannata, P.; Cortegano, I.; de Andrés, B.; Gaspar, M. L.; Cadenas, S.; Michalska, P.; León, R.; Ortiz, A.; Egido, J.; Moreno, J. A. Nrf2 Plays a Protective Role Against Intravascular Hemolysis-Mediated Acute Kidney Injury. Front. Pharmacol. 2019, 10. https://doi.org/10.3389/fphar.2019.00740.

Romero, A.; San Hipólito‐Luengo, Á.; Villalobos, L. A.; Vallejo, S.; Valencia, I.; Michalska, P.; Pajuelo‐Lozano, N.; Sánchez‐Pérez, I.; León, R.; Bartha, J. L.; Sanz, M. J.; Erusalimsky, J. D.; Sánchez‐Ferrer, C. F.; Romacho, T.; Peiró, C. The Angiotensin‐(1‐7)/Mas Receptor Axis Protects from Endothelial Cell Senescence via Klotho and Nrf2 Activation. Aging Cell 2019, 18 (3), e12913. https://doi.org/10.1111/acel.12913.

Sciú, M. L.; Sebastián-Pérez, V.; Martinez-Gonzalez, L.; Benitez, R.; Perez, D. I.; Pérez, C.; Campillo, N. E.; Martinez, A.; Moyano, E. L. Computer-Aided Molecular Design of Pyrazolotriazines Targeting Glycogen Synthase Kinase 3. J. Enzyme Inhib. Med. Chem. 2019, 34 (1), 87–96. https://doi.org/10.1080/14756366.2018.1530223.

Venter, J.; Perez, C.; van Otterlo, W. A. L.; Martínez, A.; Blackie, M. A. L. 1-Aryl-3-(4-Methoxybenzyl)Ureas as Potentially Irreversible Glycogen Synthase Kinase 3 Inhibitors: Synthesis and Biological Evaluation. Bioorg. Med. Chem. Lett. 2019, 29 (13), 1597–1600. https://doi.org/10.1016/j.bmcl.2019.04.049.

2018

Vera-Puente, O.; Rodriguez-Antolin, C.; Salgado-Figueroa, A.; Michalska, P.; Pernia, O.; Reid, B. M.; Rosas, R.; Garcia-Guede, A.; SacristÁn, S.; Jimenez, J.; Esteban-Rodriguez, I.; Martin, M. E.; Sellers, T. A.; León, R.; Gonzalez, Ví. M.; De Castro, J.; Ibanez de Caceres, I. MAFG Is a Potential Therapeutic Target to Restore Chemosensitivity in Cisplatin-Resistant Cancer Cells by Increasing Reactive Oxygen Species. Transl. Res. 2018, 200, 1–17. https://doi.org/10.1016/j.trsl.2018.06.005.

Benek, O.; Hroch, L.; Aitken, L.; Gunn-Moore, F.; Vinklarova, L.; Kuca, K.; Perez, D. I.; Perez, C.; Martinez, A.; Fisar, Z.; Musilek, K. 1-(Benzo[ d ]Thiazol-2-Yl)-3-Phenylureas as Dual Inhibitors of Casein Kinase 1 and ABAD Enzymes for Treatment of Neurodegenerative Disorders. J. Enzyme Inhib. Med. Chem. 2018, 33 (1), 665–670. https://doi.org/10.1080/14756366.2018.1445736.

Chierrito, T. P. C.; Pedersoli-Mantoani, S.; Roca, C.; Sebastian-Pérez, V.; Martínez-Gonzalez, L.; Pérez, D. I.; Perez, C.; Canales, A.; Cañada, F. J.; Campillo, N. E.; Carvalho, I.; Martinez, A. Chameleon-like Behavior of Indolylpiperidines in Complex with Cholinesterases Targets: Potent Butyrylcholinesterase Inhibitors. Eur. J. Med. Chem. 2018, 145, 431–444. https://doi.org/10.1016/j.ejmech.2018.01.007.

Cuadrado, A.; Manda, G.; Hassan, A.; Alcaraz, M. J.; Barbas, C.; Daiber, A.; Ghezzi, P.; León, R.; López, M. G.; Oliva, B.; Pajares, M.; Rojo, A. I.; Robledinos-Antón, N.; Valverde, A. M.; Guney, E.; Schmidt, H. H. H. W. Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. Pharmacol. Rev. 2018, 70 (2), 348–383. https://doi.org/10.1124/pr.117.014753.

del Cerro, P.; Alquézar, C.; Bartolomé, F.; González-Naranjo, P.; Pérez, C.; Carro, E.; Páez, J. A.; Campillo, N. E.; Martín-Requero, Á. Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease. CNS Drugs 2018, 32 (6), 579–591. https://doi.org/10.1007/s40263-018-0515-7.

Estrada Valencia, M.; Herrera-Arozamena, C.; de Andrés, L.; Pérez, C.; Morales-García, J. A.; Pérez-Castillo, A.; Ramos, E.; Romero, A.; Viña, D.; Yáñez, M.; Laurini, E.; Pricl, S.; Rodríguez-Franco, M. I. Neurogenic and Neuroprotective Donepezil-Flavonoid Hybrids with Sigma-1 Affinity and Inhibition of Key Enzymes in Alzheimer’s Disease. Eur. J. Med. Chem. 2018, 156, 534–553. https://doi.org/10.1016/j.ejmech.2018.07.026.

Figueiro-Silva, J.; Antequera, D.; Pascual, C.; de la Fuente Revenga, M.; Volt, H.; Acuña-Castroviejo, D.; Rodríguez-Franco, M. I.; Carro, E. The Melatonin Analog IQM316 May Induce Adult Hippocampal Neurogenesis and Preserve Recognition Memories in Mice. Cell Transplant. 2018, 27 (3), 423–437. https://doi.org/10.1177/0963689717721217.

Gandini, A.; Bartolini, M.; Tedesco, D.; Martinez-Gonzalez, L.; Roca, C.; Campillo, N. E.; Zaldivar-Diez, J.; Perez, C.; Zuccheri, G.; Miti, A.; Feoli, A.; Castellano, S.; Petralla, S.; Monti, B.; Rossi, M.; Moda, F.; Legname, G.; Martinez, A.; Bolognesi, M. L. Tau-Centric Multitarget Approach for Alzheimer’s Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors. J. Med. Chem. 2018, 61 (17), 7640–7656. https://doi.org/10.1021/acs.jmedchem.8b00610.

Herrera-Arozamena, C.; Martí-Marí, O.; Estrada, M.; Dela Fuente-Revenga, M.; Villalba-Galea, C. A.; Isabel Rodríguez-Franco, M. Functional Characterization of Novel Photo-Switchable Neuromuscular Blockers. Biophys. J. 2018, 114 (3), 297a. https://doi.org/10.1016/j.bpj.2017.11.1696.

Martin-de-Saavedra, M. D.; Navarro, E.; Moreno-Ortega, A. J.; Cunha, M. P.; Buendia, I.; Hernansanz-Agustín, P.; León, R.; Cano-Abad, M. F.; Martínez-Ruiz, A.; Martínez-Murillo, R.; Duchen, M. R.; López, M. G. The APPswe/PS1A246E Mutations in an Astrocytic Cell Line Leads to Increased Vulnerability to Oxygen and Glucose Deprivation, Ca 2+ Dysregulation, and Mitochondrial Abnormalities. J. Neurochem. 2018, 145 (2), 170–182. https://doi.org/10.1111/jnc.14293.

Reis, J.; Cagide, F.; Valencia, M. E.; Teixeira, J.; Bagetta, D.; Pérez, C.; Uriarte, E.; Oliveira, P. J.; Ortuso, F.; Alcaro, S.; Rodríguez-Franco, M. I.; Borges, F. Multi-Target-Directed Ligands for Alzheimer’s Disease: Discovery of Chromone-Based Monoamine Oxidase/Cholinesterase Inhibitors. Eur. J. Med. Chem. 2018, 158, 781–800. https://doi.org/10.1016/j.ejmech.2018.07.056.

Roca, C.; Requena, C.; Sebastián-Pérez, V.; Malhotra, S.; Radoux, C.; Pérez, C.; Martinez, A.; Antonio Páez, J.; Blundell, T. L.; Campillo, N. E. Identification of New Allosteric Sites and Modulators of AChE through Computational and Experimental Tools. J. Enzyme Inhib. Med. Chem. 2018, 33 (1), 1034–1047. https://doi.org/10.1080/14756366.2018.1476502.

2017

Barbado, M. V.; Medrano, M.; Caballero-Velázquez, T.; Álvarez-Laderas, I.; Sánchez-Abarca, L. I.; García-Guerrero, E.; Martín-Sánchez, J.; Rosado, I. V.; Piruat, J. I.; Gonzalez-Naranjo, P.; Campillo, N. E.; Páez, J. A.; Pérez-Simón, J. A. Cannabinoid Derivatives Exert a Potent Anti-Myeloma Activity Both in Vitro and in Vivo. Int. J. Cancer 2017, 140 (3), 674–685. https://doi.org/10.1002/ijc.30483.

Chierrito, T. P. C.; Pedersoli-Mantoani, S.; Roca, C.; Requena, C.; Sebastian-Perez, V.; Castillo, W. O.; Moreira, N. C. S.; Pérez, C.; Sakamoto-Hojo, E. T.; Takahashi, C. S.; Jiménez-Barbero, J.; Cañada, F. J.; Campillo, N. E.; Martinez, A.; Carvalho, I. From Dual Binding Site Acetylcholinesterase Inhibitors to Allosteric Modulators: A New Avenue for Disease-Modifying Drugs in Alzheimer’s Disease. Eur. J. Med. Chem. 2017, 139, 773–791. https://doi.org/10.1016/j.ejmech.2017.08.051.

Espadinha, M.; Dourado, J.; Lajarin-Cuesta, R.; Herrera-Arozamena, C.; Gonçalves, L. M. D.; Rodríguez-Franco, M. I.; de los Rios, C.; Santos, M. M. M. Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists. ChemMedChem 2017, 12 (7), 537–545. https://doi.org/10.1002/cmdc.201700037.

Fernández, S.; Giglio, J.; Reyes, A. L.; Damián, A.; Pérez, C.; Pérez, D. I.; González, M.; Oliver, P.; Rey, A.; Engler, H.; Cerecetto, H. 3-(Benzyloxy)-1-(5-[ 18 F]Fluoropentyl)-5-Nitro-1 H -Indazole: A PET Radiotracer to Measure Acetylcholinesterase in Brain. Future Med. Chem. 2017, 9 (10), 983–994. https://doi.org/10.4155/fmc-2017-0023.

Gameiro, I.; Michalska, P.; Tenti, G.; Cores, Á.; Buendia, I.; Rojo, A. I.; Georgakopoulos, N. D.; Hernández-Guijo, J. M.; Teresa Ramos, M.; Wells, G.; López, M. G.; Cuadrado, A.; Menéndez, J. C.; León, R. Discovery of the First Dual GSK3β Inhibitor/Nrf2 Inducer. A New Multitarget Therapeutic Strategy for Alzheimer’s Disease. Sci. Rep. 2017, 7 (1), 45701. https://doi.org/10.1038/srep45701.

García, A.; Brea, J.; González-García, A.; Pérez, C.; Cadavid, M. I.; Loza, M. I.; Martinez, A.; Gil, C. Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects. Molecules 2017, 22 (9), 1472. https://doi.org/10.3390/molecules22091472.

Guerra, A.; Gonzalez-Naranjo, P.; Campillo, N. E.; Varela, J.; Lavaggi, M. L.; Merlino, A.; Cerecetto, H.; González, M.; Gomez-Barrio, A.; Escario, J. A.; Fonseca-Berzal, C.; Yaluf, G.; Paniagua-Solis, J.; Páez, J. A. Novel Imidazo[4,5 -c ][1,2,6]Thiadiazine 2,2-Dioxides as Antiproliferative Trypanosoma Cruzi Drugs: Computational Screening from Neural Network, Synthesis and in Vivo Biological Properties. Eur. J. Med. Chem. 2017, 136, 223–234. https://doi.org/10.1016/j.ejmech.2017.04.075.

Herrera-Arozamena, C.; Martí-Marí, O.; de la Fuente Revenga, M.; Villalba-Galea, C. A.; Rodríguez-Franco, M. I. New Photoswitchable Neuromuscular Blockers: Design, Synthesis, and Physicochemical / Biological Evaluation. J. Neurochem. 2017, 142, 123. https://doi.org/10.1111/jnc.14093.

Mansilla, A.; Chaves-Sanjuan, A.; Campillo, N. E.; Semelidou, O.; Martínez-González, L.; Infantes, L.; González-Rubio, J. M.; Gil, C.; Conde, S.; Skoulakis, E. M. C.; Ferrús, A.; Martínez, A.; Sánchez-Barrena, M. J. Interference of the Complex between NCS-1 and Ric8a with Phenothiazines Regulates Synaptic Function and Is an Approach for Fragile X Syndrome. Proc. Natl. Acad. Sci. 2017, 114 (6), E999–E1008. https://doi.org/10.1073/pnas.1611089114.

Monjas, L.; Arce, M. P.; León, R.; Egea, J.; Pérez, C.; Villarroya, M.; López, M. G.; Gil, C.; Conde, S.; Rodríguez-Franco, M. I. Enzymatic and Solid-Phase Synthesis of New Donepezil-Based L- and d -Glutamic Acid Derivatives and Their Pharmacological Evaluation in Models Related to Alzheimer’s Disease and Cerebral Ischemia. Eur. J. Med. Chem. 2017, 130, 60–72. https://doi.org/10.1016/j.ejmech.2017.02.034.

Morales-García, J. A.; de la Fuente Revenga, M.; Alonso-Gil, S.; Rodríguez-Franco, M. I.; Feilding, A.; Perez-Castillo, A.; Riba, J. The Alkaloids of Banisteriopsis Caapi, the Plant Source of the Amazonian Hallucinogen Ayahuasca, Stimulate Adult Neurogenesis in Vitro. Sci. Rep. 2017, 7 (1), 5309. https://doi.org/10.1038/s41598-017-05407-9. Altmetric score (which calculates a score based on the attention given to an article): 176. This article is in the 98^th percentile (ranked 4,254^th) of the 279,324 tracked articles of a similar age in all journals and the 97^th percentile (ranked 13^th) of the 499 tracked articles of a similar age in Scientific Reports, (https://www.nature.com/articles/s41598-017-05407-9/metrics, accessed January 13, 2022).

Palomo, V.; Perez, D. I.; Roca, C.; Anderson, C.; Rodríguez-Muela, N.; Perez, C.; Morales-Garcia, J. A.; Reyes, J. A.; Campillo, N. E.; Perez-Castillo, A. M.; Rubin, L. L.; Timchenko, L.; Gil, C.; Martinez, A. Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases. J. Med. Chem. 2017, 60 (12), 4983–5001. https://doi.org/10.1021/acs.jmedchem.7b00395.

Ponzoni, I.; Sebastián-Pérez, V.; Requena-Triguero, C.; Roca, C.; Martínez, M. J.; Cravero, F.; Díaz, M. F.; Páez, J. A.; Arrayás, R. G.; Adrio, J.; Campillo, N. E. Hybridizing Feature Selection and Feature Learning Approaches in QSAR Modeling for Drug Discovery. Sci. Rep. 2017, 7 (1), 2403. https://doi.org/10.1038/s41598-017-02114-3.

Punzón, E.; García-Alvarado, F.; Maroto, M.; Fernández-Mendívil, C.; Michalska, P.; García-Álvarez, I.; Arranz-Tagarro, J. A.; Buendia, I.; López, M. G.; León, R.; Gandía, L.; Fernández-Mayoralas, A.; García, A. G. Novel Sulfoglycolipid IG20 Causes Neuroprotection by Activating the Phase II Antioxidant Response in Rat Hippocampal Slices. Neuropharmacology 2017, 116, 110–121. https://doi.org/10.1016/j.neuropharm.2016.12.016.

Efentakis, P.; Rizakou, A.; Christodoulou, E.; Chatzianastasiou, A.; López, M. G.; León, R.; Balafas, E.; Kadoglou, N. P. E.; Tseti, I.; Skaltsa, H.; Kostomitsopoulos, N.; Iliodromitis, E. K.; Valsami, G.; Andreadou, I. Saffron (Crocus sativus) intake provides nutritional preconditioning against myocardial ischemia-reperfusion injury in wild type and Apo-E(-/-) mice: Involvement of Nrf2 activation. Nut., Met. & Card. Dis., 2017, 27, 919-929. https://doi.org/10.1016/j.numecd.2017.08.005.

Michalska, P.; Buendia, I.; Del Barrio, L.; León, R. Novel multitarget hybrid compounds for the treatment of Alzheimer’s disease. Curr. Top. Med. Chem. 2017, 19, 1027-1043. https://doi.org/10.2174/1568026616666160927154116

Rieger, D. K.; Navarro, E.; Buendia, I.; Parada, E.; González-Lafuente, L.; León, R.; Costa, A. P.; Heinrich, I. A.; Nascimento, K. S.; Cavada, B. S.; López, M. G.; Egea, J.; Leal, R. B. ConBr, a lectin purified from the seeds of Canavalia brasileiensis, protects against ischemia in organotypic culture of rat hippocampus: Potential implication of voltage gated calcium channels. Neurochemical Research, 2017, 42, 347-359. https://doi.org/10.1007/s11064-016-2078-7

Buendia, I.; Tenti, G.; Michalska, P.; Méndez-López, I.; Luengo, E.; Satriani, M.; Padín-Nogueira, F.; López, M. G.; Ramos, M. T.; García, A. G.; Menéndez, J. C.; León, R. ITH14001, a CGP37157-nimodipine hybrid designed to regulate calcium homeostasis and oxidative stress, exerts neuroprotection in cerebral ischemia. ACS Chem. Neurosci. 2017, 8, 67-81. https://doi.org/10.1021/acschemneuro.6b00181

Michalska, P.; Wojnicz, A.; Ruiz-Nuño, A.; Abril, S.; Buendia, I.; León, R. Inclusion complex of ITH12674 with 2-hydroxypropyl-b-cyclodextrin: Preparation, physical characterization and pharmacological effect. Carbohydrate Polymers, 2017, 157, 94-104. https://doi.org/10.1016/j.carbpol.2016.09.072

2016

Benchekroun, M.; Romero, A.; Egea, J.; León, R.; Michalska, P.; Buendía, I.; Jimeno, M. L.; Jun, D.; Janockova, J.; Sepsova, V.; Soukup, O.; Bautista-Aguilera, O. M.; Refouvelet, B.; Ouari, O.; Marco-Contelles, J.; Ismaili, L. The Antioxidant Additive Approach for Alzheimer’s Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators. J. Med. Chem. 2016, 59 (21), 9967–9973. https://doi.org/10.1021/acs.jmedchem.6b01178.

Chlebek, J.; De Simone, A.; Hošťálková, A.; Opletal, L.; Pérez, C.; Pérez, D. I.; Havlíková, L.; Cahlíková, L.; Andrisano, V. Application of BACE1 Immobilized Enzyme Reactor for the Characterization of Multifunctional Alkaloids from Corydalis Cava (Fumariaceae) as Alzheimer’s Disease Targets. Fitoterapia 2016, 109, 241–247. https://doi.org/10.1016/j.fitote.2016.01.008.

Chlebek, J.; Novák, Z.; Kassemová, D.; Šafratová, M.; Kostelník, J.; Malý, L.; Ločárek, M.; Opletal, L.; Hošt’álková, A.; Hrabinová, M.; Kuneš, J.; Novotná, P.; Urbanová, M.; Nováková, L.; Macáková, K.; Hulcová, D.; Solich, P.; Pérez Martín, C.; Jun, D.; Cahlíková, L. Isoquinoline Alkaloids from Fumaria Officinalis L. and Their Biological Activities Related to Alzheimer ’s Disease. Chem. Biodivers. 2016, 13 (1), 91–99. https://doi.org/10.1002/cbdv.201500033.

Estrada, M.; Herrera-Arozamena, C.; Pérez, C.; Viña, D.; Romero, A.; Morales-García, J. A.; Pérez-Castillo, A.; Rodríguez-Franco, M. I. New Cinnamic – N-Benzylpiperidine and Cinnamic – N,N-Dibenzyl(N-Methyl)Amine Hybrids as Alzheimer-Directed Multitarget Drugs with Antioxidant, Cholinergic, Neuroprotective and Neurogenic Properties. Eur. J. Med. Chem. 2016, 121, 376–386. https://doi.org/10.1016/j.ejmech.2016.05.055.

Estrada, M.; Pérez, C.; Soriano, E.; Laurini, E.; Romano, M.; Pricl, S.; Morales-García, J. A.; Pérez-Castillo, A.; Rodríguez-Franco, M. I. New Neurogenic Lipoic-Based Hybrids as Innovative Alzheimer’s Drugs with σ-1 Agonism and β-Secretase Inhibition. Future Med. Chem. 2016, 8 (11), 1191–1207. https://doi.org/10.4155/fmc-2016-0036.

Herrera-Arozamena, C.; Martí-Marí, O.; Estrada, M.; de la Fuente Revenga, M.; Rodríguez-Franco, M. Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases. Molecules 2016, 21 (9), 1165. https://doi.org/10.3390/molecules21091165.

Buendia, I.; Parada, E.; Navarro, E.; León, R.; Negredo, P.; Egea. J.; López, M. G. Subthreshold concentrations of melatonin and galantamine improves pathological AD-hallmarks in hippocampal organotypic cultures. Mol. Neurobiol. 2016, 53, 3338-3348. https://doi.org/10.1007/s12035-015-9272-5.

Buendia, I.; Michalska, P.; Navarro, E.; Gameiro, I.; Egea, J.; León, R. Nrf2-ARE pathway: an emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther. 2016, 157, 84-104. https://doi.org/10.1016/j.pharmthera.2015.11.003

2015

Benchekroun, M.; Bartolini, M.; Egea, J.; Romero, A.; Soriano, E.; Pudlo, M.; Luzet, V.; Andrisano, V.; Jimeno, M.-L.; López, M. G.; Wehle, S.; Gharbi, T.; Refouvelet, B.; de Andrés, L.; Herrera-Arozamena, C.; Monti, B.; Bolognesi, M. L.; Rodríguez-Franco, M. I.; Decker, M.; Marco-Contelles, J.; Ismaili, L. Novel Tacrine-Grafted Ugi Adducts as Multipotent Anti-Alzheimer Drugs: A Synthetic Renewal in Tacrine-Ferulic Acid Hybrids. ChemMedChem 2015, 10 (3), 523–539. https://doi.org/10.1002/cmdc.201402409.

Buendia, I.; Egea, J.; Parada, E.; Navarro, E.; León, R.; Rodríguez-Franco, M. I.; López, M. G. The Melatonin–N,N-Dibenzyl(N-Methyl)Amine Hybrid ITH91/IQM157 Affords Neuroprotection in an in Vitro Alzheimer’s Model via Hemo-Oxygenase-1 Induction. ACS Chem. Neurosci. 2015, 6 (2), 288–296. https://doi.org/10.1021/cn5002073.

de la Fuente Revenga, M.; Balle, T.; Jensen, A. A.; Frølund, B. Conformationally Restrained Carbamoylcholine Homologues. Synthesis, Pharmacology at Neuronal Nicotinic Acetylcholine Receptors and Biostructural Considerations. Eur. J. Med. Chem. 2015, 102, 352–362. https://doi.org/10.1016/j.ejmech.2015.07.029.

de la Fuente Revenga, M.; Fernández-Sáez, N.; Herrera-Arozamena, C.; Morales-García, J. A.; Alonso-Gil, S.; Pérez-Castillo, A.; Caignard, D.-H.; Rivara, S.; Rodríguez-Franco, M. I. Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential. J. Med. Chem. 2015, 58 (12), 4998–5014. https://doi.org/10.1021/acs.jmedchem.5b00245. This work received the honour of being the subject of the Cover of the Journal of Medicinal Chemistry for its issue of July 23, 2015 (http://pubs.acs.org/toc/jmcmar/58/14).

de la Fuente Revenga, M.; Herrera-Arozamena, C.; Fernández-Sáez, N.; Barco, G.; García-Orue, I.; Sugden, D.; Rivara, S.; Rodríguez-Franco, M. I. New Coumarin-Based Fluorescent Melatonin Ligands. Design, Synthesis and Pharmacological Characterization. Eur. J. Med. Chem. 2015, 103, 370–373. https://doi.org/10.1016/j.ejmech.2015.09.003.

de la Fuente Revenga, M.; Pérez, C.; Morales-García, J. A.; Alonso-Gil, S.; Pérez-Castillo, A.; Caignard, D.-H.; Yáñez, M.; Gamo, A. M.; Rodríguez-Franco, M. I. Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy-1,2,3,4-Tetrahydro-β-Carboline (Pinoline) and Melatonin–Pinoline Hybrids. ACS Chem. Neurosci. 2015, 6 (5), 800–810. https://doi.org/10.1021/acschemneuro.5b00041. This work received the honour of being the Cover of ACS Chemical Neuroscience in its issue of May 2015 (http://pubs.acs.org/toc/acncdm/6/5).

Matos, M. J.; Rodríguez-Enríquez, F.; Borges, F.; Santana, L.; Uriarte, E.; Estrada, M.; Rodríguez-Franco, M. I.; Laguna, R.; Viña, D. 3-Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases. ChemMedChem 2015, 10 (12), 2071–2079. https://doi.org/10.1002/cmdc.201500408.

Matos, M. J.; Rodríguez-Enríquez, F.; Vilar, S.; Santana, L.; Uriarte, E.; Hripcsak, G.; Estrada, M.; Rodríguez-Franco, M. I.; Viña, D. Potent and Selective MAO-B Inhibitory Activity: Amino- versus Nitro-3-Arylcoumarin Derivatives. Bioorg. Med. Chem. Lett. 2015, 25 (3), 642–648. https://doi.org/10.1016/j.bmcl.2014.12.001.

Pérez, C.; Ruiz del Castillo, M. L.; Gil, C.; Blanch, G. P.; Flores, G. Supercritical Fluid Extraction of Grape Seeds: Extract Chemical Composition, Antioxidant Activity and Inhibition of Nitrite Production in LPS-Stimulated Raw 264.7 Cells. Food Funct. 2015, 6 (8), 2607–2613. https://doi.org/10.1039/C5FO00325C.

Silva, T.; Bravo, J.; Summavielle, T.; Remião, F.; Pérez, C.; Gil, C.; Martínez, A.; Borges, F. Biology-Oriented Development of Novel Lipophilic Antioxidants with Neuroprotective Activity. RSC Adv. 2015, 5 (21), 15800–15811. https://doi.org/10.1039/C4RA15164J.

Egea, J.; Buendia, I.; Parada, E.; Navarro, E.; Rada, P.; Cuadrado, A.; López, M. G.; García, A. G. León, R. Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a “Drug-Prodrug” mechanism of action. Brit. J. Pharmacol. 2015, 172, 1807-1821. https://doi.org/10.1111/bph.13025.

Buendia, I.; Gomez-Rangel, V.; Gonzalez-Lafuente, L.; Parada, E.; León, R.; Gameiro, I.; Michalska, P.; Laudon, M.; Egea, J.; López, M. G. Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models. Neuropharmacol. 2015, 99, 187-195. https://doi.org/10.1016/j.neuropharm.2015.07.014

Navarro, E.; Buendia, I.; Parada, E.; León, R.; Jansen-Duerr, P.; Pircher, H.; Egea, J.; López, M. G. Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction. Biochem. Pharmacol. 2015, 97 (4), 473-81. https://doi.org/10.1016/j.bcp.2015.07.022

Egea, J.; Buendia, I.; Parada, E.; Navarro, E.; León, R.; López, M. G. Anti-inflammatory role of microglial 7 nAChRs and its role in neuroprotection. Biochem. Pharmacol. 2015, 97 (4), 463-72. https://doi.org/10.1016/j.bcp.2015.07.032

PATENTS

Duarte, P., Crisman, E., Michalska, P., Cuadrado, A., Léon, R. Compuestos inductores de Nrf2 e inhibidores de MAO-B para el tratamiento de la enfermedad de Parkinson. Spanish Patent Application: P202230025 (January, 14, 2022).

Cuadrado Pastor, A.; Fernández Ginés, R.; Encinar, J. A.; León, R.; Franco González, J. F.; García López, M.; Rodríguez Franco, M. I.; Rojo Sanchís, A. I. An inhibitor of the interaction between NRF2 and beta-TrCP for therapy of diseases presenting chronic or acute inflammation / Treatment of NRF2-related diseases. European Patent Application EP21382025.1 (January 15, 2021).

Perez-Simon, J.A.; Barbado, M.V.; Medrano, M.; Campillo, N. E.; Páez, J. A.; Gonzalez-Naranjo, P. Indazole derivatives for cancer treatment. P201630539 (April 27, 2016); PCT/ES2017/070261, WO2017/186999 (April 27, 2017); US Application 16/097,149 (October 26, 2018); European Patent 17788869.0-1109/3449922 (November 29, 2019). Exclusive License Agreement with Entourage Biosciences, a company of British Columbia, Vancouver, Canada.

Ibañez, I., de Castro, J., Vera, O., Pernia, O., Rodriguez, C., Gonzalez, V., Martin, M. E., Salgado, A., Michalska, P., León, R. MAFG as a potential therapeutic target to restore chemosensitivity in platinum-resistant cancer cells. European Patent Application WO2019/052708 (March, 21, 2019)

León, R., Abril, S., Duarte, P., Crisman, E., Michalska, P., Salaices, M., Menéndez, J. C. Compuestos agonistas nicotínicos y antioxidantes para el tratamiento de enfermedades neurodegenerativas. Spanish Patent Application: ES2819309 (October, 14, 2019)

León, R., Abril, S., Michalska, P., Buendia, I., Salaices, M., Menéndez, J. C., G. López, M. Compuestos derivados de 2-iodo-7-(((2-(5-metoxi-1H-indol-3-il)etil)amino)metil)-1-alquil/aril-6,7,7a,8-tetrahidro-3H-pirrolo[2,1-j]quinolina-3,9(5H)-diona como antioxidantes, inductores de Nrf2 y moduladores nicotínicos para el tratamiento de enfermedades neurodegenerativas. Spanish Patent Application: ES2781377 (March, 01, 2019)

León, R., Campello, L., Michalska, P., Noailles, A., Kutsyr, O., Fernández, L., Maneu, V., Lax, P., García, A., Cuenca, N. Uso del 3-(2-isotiocianatoetil)-5-metoxi-1H-indol para el tratamiento de las enfermedades degenerativas de la retina. Spanish Patent Application: ES2737709. European Patent Application: WO2020/012052. (July, 11, 2019)

León, R., Buendia, I., Navarro, E., Michalska, P., Gameiro, I., López, A., Egea, J., G. López, M., G. García., A. Compounds derived from 3-Alkylamino-1H-indole acrylate, and the use thereof in the treatment of neurodegenerative diseases. European Patent Application: EP3208262 USA application: US2018/0105492 Canada application: CA2964309. (April, 11, 2017)

León, R., Tenti, G., Gameiro, I., Michalska, P., Buendia, I., Hernández, J. M., Ramos, M. T., Menéndez, J. C., García, A. Uso de los derivados 4H-pirano[2,3-c]pirazol en el tratamiento de enfermedades neurodegenerativas. Spanish Patent Application: ES2659828. (February, 15, 2016)

León, R., Gameiro, I., Tenti, G., Michalska, P., Buendia, I., Abril, S., García, M., Ramos, M. T., Menéndez, J. C., García, A. Uso de los compuestos derivados de 3-alquil-4-aril-1,4,6,7,8,9-hexahidropirazolo[4´,3´:5,6]pirano[2,3-b]quinolin-5-amina inhibidores duales de GSK3b – AChE y su uso en el tratamiento de enfermedades neurodegenerativas. Spanish Patent Application: ES2587137A2. (April, 20, 2015)

Páez, J. A.; Campillo, N. E.; Pérez, C.; González-Naranjo, P.; Pérez-Macias, N.; de Ceballos, M. L.; Martín-Requero, A.; Alquézar, C.; Martín, M. I.; Girón, R.; Sánchez-Robles, E.; Romero, J. Nueva familia de derivados carbonílicos de 1-indazolilo con propiedades cannabinoides y/o colinérgicas y/o reguladoras del péptido beta-amiloide. PCT/ES2016/070906 (December 18, 2015).

AItenea Biotech (www.aitenea.es) Juan A. Páez (Scientific Adviser)