The development of CNS-active LRRK2 inhibitors using property-directed optimisation |
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| Authors: | Madeline E. Kavanagh Munikumar Reddy Doddareddy Michael Kassiou |
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| Affiliation: | 1. School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia;2. Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia;3. Brain and Mind Research Institute, Sydney, NSW 2050, Australia;4. Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia |
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| Abstract: | Mutations in PARK8/LRRK2 are the most common genetic cause of Parkinson’s disease. Inhibition of LRRK2 kinase activity has neuroprotective benefits, and provides a means of addressing the underlying biochemical cause of Parkinson’s disease for the first time. Initial attempts to develop LRRK2 inhibitors were largely unsuccessful and highlight shortcomings intrinsic to traditional, high throughput screening methods of lead discovery. Recently, amino-pyrimidine GNE-7915 was reported as a potent (IC50 = 9 nM) selective (1/187 kinases), brain-penetrant and non-toxic inhibitor of LRRK2. The use of in silico modelling, extensive in vitro assays and resource-efficient in vivo techniques to produce GNE-7915, reflects a trend towards the concerted optimisation of potency, selectivity and pharmacokinetic properties in early-stage drug development. |
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| Keywords: | LRRK2 Kinase inhibitor Parkinson’s disease Structure–property relationships CNS MPO Ligand efficiency |
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