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
| Autor: | Ravi G. Kurumbail, Patrick Robert Verhoest, Stefanus J. Steyn, Zdenek Berger, Travis T. Wager, Bethany L. Kormos, Jayasankar Jasti, Paul Galatsis, Jaclyn Louise Henderson, Warren D. Hirst, Elie Needle, Yi Chen, Karen J. Coffman, G. Stephen Noell, Christopher Houle, Matthew Merrill Hayward |
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| Rok vydání: | 2014 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 58:419-432 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm5014055 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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