Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

Katarzyna Grychowska (1) , Agnieszka Olejarz-Maciej (1) , Klaudia Blicharz (1) , Wojciech Pietruś (2) , Tadeusz Karcz (1) , Rafał Kurczab (2) , Paulina Koczurkiewicz (1) , Agata Doroz-Płonka (1) , Gniewomir Latacz (1) , Abdul Raheem Keeri (1) , Kamil Piska (1) , Grzegorz Satała (2) , Joanna Pęgiel (1) , Wojciech Trybała (1) , Magdalena Jastrzębska-Więsek (1) , Andrzej Bojarski (2) , Frédéric Lamaty (3) , Anna Partyka (1) , Maria Walczak (1) , Martyna Krawczyk (2) , Natalia Malikowska-Racia (2) , Piotr Popik (2) , Paweł Zajdel (1)

1 UJ - Uniwersytet Jagielloński w Krakowie = Jagiellonian University
2 PAN - Polska Akademia Nauk = Polish Academy of Sciences = Académie polonaise des sciences
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.

Mots clés: Alzheimer's disease; MAO-B inhibitors; Glia; Cognition; Fluorinated compounds; hERG channel

Domaines: Chimie thérapeutique

Katarzyna Grychowska, Agnieszka Olejarz-Maciej, Klaudia Blicharz, Wojciech Pietruś, Tadeusz Karcz, et al.. Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines. European Journal of Medicinal Chemistry, 2022, 236, pp.114329. ⟨10.1016/j.ejmech.2022.114329⟩. ⟨hal-03648220⟩