Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10595493 | Bioorganic & Medicinal Chemistry Letters | 2013 | 7 Pages |
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 (IC50Â =Â 9Â 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.
Keywords
SARDLP1PARK8SBDDTTK4E-BPLRRK2FOXO1HTSParkinson’s diseaseSPRleucine-rich repeat kinase 2CNSStructure–activity relationshipStructure–property relationshipsStructure–property relationshipBBBBlood–brain barriercentral nervous systemStructure-based drug designhigh throughput screeningKinase inhibitordynamin-like protein 1Ligand efficiency
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Madeline E. Kavanagh, Munikumar Reddy Doddareddy, Michael Kassiou,