The development of CNS-active LRRK2 inhibitors using property-directed optimisation

19Citations
Citations of this article
43Readers
Mendeley users who have this article in their library.

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. © 2013 Elsevier Ltd. All rights reserved.

Cite

CITATION STYLE

APA

Kavanagh, M. E., Doddareddy, M. R., & Kassiou, M. (2013, July 1). The development of CNS-active LRRK2 inhibitors using property-directed optimisation. Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2013.04.086

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free