Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease
Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress. ; This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2019-106285RB), the Basque Government (IT1211/19) and Generalitat de Catalunya (GC) (2017SGR106). The project leading to these results has received funding from "la Caixa" Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union's Horizon 2020 research and innovation programme. C.G.-F, F.V., C.E., S.R.-A., A.B., and M.P. Financial support was provided for F.V. (University of Barcelona, APIF_2017), S.R.-A. (Generalitat de Catalunya, 2018FI_B_00227), A.B. (Institute of Biomedicine UB_2018), J.A.G.-S. is a member emeritus of the Institut d'Estudis Catalans (Barcelona, Catalonia). E.H.-H. is supported by a predoctoral scholarship (FPI/2102/2018; Consejería de Innovación, Investigación y Turismo del Gobierno de las Islas Baleares y del Fondo Social Europeo). M.R., T.D., and K.N. kindly acknowledge the project funded by the Ministry of Science and Technological Development of the Republic of Serbia, Contract No. 451-03-68/2020-14/200161, and HORISON 2020-COST-Action CA18133 ERNEST: European Research Network on Signal Transduction. E. M. acknowledges funding to Severo Ochoa: CEX2019-917S. M.I.L, A.L.M. and J.B. gratefully acknowledge support from Xunta de Galicia (ED431C 2018/21 and ED431G 2019/02) and European Regional Development Fund (ERDF). ; With funding from the Spanish government through the 'Severo Ochoa Centre of Excellence' accreditation (CEX2019-000917-S). ; Peer reviewed