Back to Search
Start Over
Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor
- Source :
- Journal of Medicinal Chemistry. 58:419-432
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
Abstract
- Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.
- Subjects :
- Models, Molecular
Proteome
Molecular Sequence Data
Drug Evaluation, Preclinical
Mutation, Missense
Mice, Transgenic
Total population
Protein Serine-Threonine Kinases
Pharmacology
Leucine-rich repeat
Crystallography, X-Ray
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
chemistry.chemical_compound
In vivo
Nitriles
Drug Discovery
Animals
Humans
Pyrroles
Kinome
Amino Acid Sequence
Kinase activity
Protein Kinase Inhibitors
Molecular Structure
Kinase
Brain
Parkinson Disease
LRRK2
Protein Structure, Tertiary
Rats
nervous system diseases
Mice, Inbred C57BL
Benzonitrile
HEK293 Cells
Pyrimidines
chemistry
Area Under Curve
Molecular Medicine
Protein Binding
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....85d07c27f7b39f821bc72af5c98828c6