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Papers of the Week


Papers: 18 Jan 2025 - 24 Jan 2025


2025 Jan 17


J Med Chem


39818939

Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties.

Authors

Bagán A, López-Ruiz A, Abás S, Ruiz-Cantero MC, Vasilopoulou F, Taboada-Jara T, Griñán-Ferré C, Pallàs M, Muguruza C, Diez-Alarcia R, Callado LF, Entrena JM, Cobos EJ, Pérez B, Morales-García JA, Molins E, De Jonghe S, Daelemans D, Brea J, Val C, Loza MI, Hernández-Hernández E, García-Sevilla JA, García-Fuster MJ, Díaz C, Fernández-Godino R, Genilloud O, Beljkaš M, Oljačić S, Nikolic K, Escolano C

Abstract

Imidazoline receptors (I-IRs) are altered in Alzheimer’s disease (AD) patients and are associated with analgesia. I-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-2-pyrrol-2-yl)phosphonates endowed with relevant affinities for I-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its 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 I-IRs as an innovative approach for therapeutics.