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
Jul 15, 1999·Structure·X ZhuK A Morgenstern
Mar 24, 2009·Journal of Neurochemistry·Christian Johannes GloecknerMarius Ueffing
Dec 3, 2009·Neuropharmacology·Lenka Munoz, Alaina J Ammit
Jun 28, 2011·Nature Reviews. Drug Discovery·David C Swinney, Jason Anthony
Aug 26, 2011·Cell Death & Disease·M LichtenbergD C Rubinsztein
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
Mar 1, 2012·Neuropharmacology·Louise M CollinsYvonne M Nolan
Apr 28, 2012·Cell Death and Differentiation·C-Y ChenH-L Wang
Sep 19, 2012·Journal of Medicinal Chemistry·Anthony A EstradaZachary K Sweeney
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
Citations
Dec 10, 2015·Journal of Neuroinflammation·Isabella RussoElisa Greggio
Jul 2, 2016·International Journal of Molecular Sciences·Eleonora Da PozzoClaudia Martini
Aug 4, 2018·Neurological Research·Weipeng ZhengShifeng Wen
Jan 16, 2019·PloS One·Judong KimEunsook Lee
Aug 20, 2016·Chemistry : a European Journal·Yi-An ChenPi-Tai Chou
May 8, 2021·Biochemical Society Transactions·Alice FilippiniIsabella Russo
Oct 13, 2017·Journal of Medicinal Chemistry·Douglas S WilliamsonKenneth V Christensen
Sep 6, 2017·The Journal of Organic Chemistry·Xiaoxia WangHonghua Rao
May 15, 2020·The Journal of Organic Chemistry·Koppanathi NagarajuKwunmin Chen
Sep 25, 2021·Photochemistry and Photobiology·Yanjing WangJohn-Stephen Taylor