RT Journal Article
T1 Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2<i>H</i>-pyrrol-2-yl) phosphonates as Imidazoline <i>I</i><sub>2</sub> receptor ligands with anti-Alzheimer and analgesic properties
A1 Bagán, Andrea
A1 López Ruiz, Alba
A1 Abás Prades, Sònia
A1 Ruiz Cantero, M. Carmen
A1 Vasilopoulou, Foteini
A1 Taboada Jara, Teresa
A1 Griñán Ferré, Christian
A1 Pallàs, Mercè
A1 Muguruza Millán, Carolina
A1 Díez Alarcia, Rebeca
A1 Callado Hernando, Luis Felipe
A1 Entrena Fernández, José Manuel
A1 Cobos del Moral, Enrique José
A1 Pérez Fernández, Belén
A1 Morales García, José A.
A1 Molins, Elies
A1 Jonghe, Steven De
A1 Daelemans, Dirk
A1 Brea Floriani, José Manuel
A1 Val García, Cristina
A1 Loza García, María Isabel
A1 Hernández Hernández, Elena
A1 García Sevilla, Jesús A.
A1 García-Fuster, M. Julia
A1 Díaz Navarro, Caridad
A1 Fernández Godino, Rosario
A1 Genilloud, Olga
A1 Beljkaš, Milan
A1 Oljačić, Slavica
A1 Nikolic, Katarina
A1 Escolano Mirón, Carmen
K1 Ligands
K1 Phenyls
K1 Plasma
K1 Selectivity
K1 Substituents
AB Imidazoline I2 receptors (I2-IRs) are altered in Alzheimer’s disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics
PB ACS Publications
YR 2025
FD 2025-01-17
LK https://hdl.handle.net/10347/45592
UL https://hdl.handle.net/10347/45592
LA eng
NO Andrea Bagán, Alba López-Ruiz, Sònia Abás, M. Carmen Ruiz-Cantero, Foteini Vasilopoulou, Teresa Taboada-Jara, Christian Griñán-Ferré, Mercè Pallàs, Carolina Muguruza, Rebeca Diez-Alarcia, Luis F. Callado, José M. Entrena, Enrique J. Cobos, Belén Pérez, José A. Morales-García, Elies Molins, Steven De Jonghe, Dirk Daelemans, José Brea, Cristina Val, M. Isabel Loza, Elena Hernández-Hernández, Jesús A. García-Sevilla, M. Julia García-Fuster, Caridad Díaz, Rosario Fernández-Godino, Olga Genilloud, Milan Beljkaš, Slavica Oljačić, Katarina Nikolic, and Carmen Escolano. Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties. Journal of Medicinal Chemistry 2025 68 (3), 2551-2573 DOI: 10.1021/acs.jmedchem.4c01644
NO This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2022-1380790B-I00 to C.E., and PID2021-138079OB-I00 to M.P.; MICIU/AEI/10.13039/501100011033 and FEDER, UE; and PDC2022-133441-I00 to C.E.; MICIU/AEI/10.13039/501100011033 Europea Next GenerationEU/PRTR), Basque Government (IT-1512-22) and Generalitat de Catalunya (2021 SGR 00357). Financial support was provided for A.L.-R. (PRE2022-105091 ministerio de Ciencia e Innovación). E.H.-H. was first funded by the Margarita Salas Program (Ministerio de Universidades; Plan de Recuperación, Transformación y Resilencia; NextGenerationEU) with the participation of the University of the Balearic Islands, and currently holds grant FJC2022-048338-I, funded by MCIN/AEI/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR. The authors acknowledge grant support from the Ministry of Science and Innovation, Spain, with funds from the European Union NextGenerationEU (PRTRC17.I1) and the Autonomous Community of Galicia within the framework of the 2023 Biotechnology Plan Applied to Health, Xunta de Galicia (ED431C 2022/20) and the European Regional Development Fund (ERDF). This study was partially supported by the Andalusian Regional Government (grant CTS-109). Authors also thank the support of the Unit of Excellence “UNETE” from the University of Granada (reference UCE-PP2017-05). M.B., S.O., and K.N. acknowledge the Ministry of Science, Technological Development and Innovation, Republic of Serbia through two Grant Agreements with University of Belgrade-Faculty of Pharmacy No. 451-03-65/2024-03/200161 and No. 451-03-66/2024-03/200161. A.L. thanks to Grant PRE2022-105091 funded by MICIU/AEI/10.13039/501100011033
DS Minerva
RD 28 abr 2026