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.
Copyright policy )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.
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.
- Pfizer (United States) United States
Models, Molecular, Molecular Structure, Molecular Sequence Data, Drug Evaluation, Preclinical, Mutation, Missense, Brain, Mice, Transgenic, Parkinson Disease, Crystallography, X-Ray, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mice, Inbred C57BL, HEK293 Cells, Area Under Curve, Drug Discovery, Nitriles, Animals, Humans, Amino Acid Sequence, Protein Kinase Inhibitors, Protein Binding
Models, Molecular, Molecular Structure, Molecular Sequence Data, Drug Evaluation, Preclinical, Mutation, Missense, Brain, Mice, Transgenic, Parkinson Disease, Crystallography, X-Ray, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mice, Inbred C57BL, HEK293 Cells, Area Under Curve, Drug Discovery, Nitriles, Animals, Humans, Amino Acid Sequence, Protein Kinase Inhibitors, Protein Binding
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