Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation

European Journal of Medicinal Chemistry
Lenka MunozMichael Kassiou

Abstract

LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti-neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.

References

Dec 3, 2009·Neuropharmacology·Lenka Munoz, Alaina J Ammit
Jun 28, 2011·Nature Reviews. Drug Discovery·David C Swinney, Jason Anthony
Oct 25, 2011·Nature Reviews. Cancer·Michael J DevineNicholas W Wood
Feb 4, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Mark S MoehleAndrew B West
Sep 20, 2012·Biochemical Society Transactions·Nicolas Dzamko, Glenda M Halliday
Jun 1, 2013·Bioorganic & Medicinal Chemistry Letters·Madeline E KavanaghMichael Kassiou
Feb 18, 2014·Experimental Neurology·Erik Ellwardt, Frauke Zipp

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Citations

Jul 2, 2016·International Journal of Molecular Sciences·Eleonora Da PozzoClaudia Martini
May 8, 2021·Biochemical Society Transactions·Alice FilippiniIsabella Russo
May 15, 2020·The Journal of Organic Chemistry·Koppanathi NagarajuKwunmin Chen

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