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Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Apr 07; Vol. 6 (5), pp. 584-9. Date of Electronic Publication: 2015 Apr 07 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5-chloropyrrolopyrimidine, JH-II-127 (18), as a potent and selective inhibitor of both wild-type and G2019S mutant LRRK2. Compound 18 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 μM in a variety of cell types and is capable of inhibiting Ser935 phosphorylation in mouse brain following oral delivery of doses as low as 30 mg/kg.
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26005538
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.5b00064