pf-06447475 and Parkinson-Disease

pf-06447475 has been researched along with Parkinson-Disease* in 2 studies

Other Studies

2 other study(ies) available for pf-06447475 and Parkinson-Disease

Article	Year
Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate. Journal of medicinal chemistry, 2020, 03-12, Volume: 63, Issue:5 Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds Topics: Animals; Benzothiazoles; Cells, Cultured; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Neurogenesis; Oligodendroglia; Parkinson Disease; Protein Kinase Inhibitors; Wnt Signaling Pathway	2020
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. Journal of medicinal chemistry, 2015, Jan-08, Volume: 58, Issue:1 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. Topics: Amino Acid Sequence; Animals; Area Under Curve; Brain; Crystallography, X-Ray; Drug Discovery; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutation, Missense; Nitriles; Parkinson Disease; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proteome; Pyrimidines; Pyrroles; Rats	2015

Article

Year

Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate.

Journal of medicinal chemistry, 2020, 03-12, Volume: 63, Issue:5

Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds

Topics: Animals; Benzothiazoles; Cells, Cultured; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Neurogenesis; Oligodendroglia; Parkinson Disease; Protein Kinase Inhibitors; Wnt Signaling Pathway

2020

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.

Journal of medicinal chemistry, 2015, Jan-08, Volume: 58, Issue:1

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.

Topics: Amino Acid Sequence; Animals; Area Under Curve; Brain; Crystallography, X-Ray; Drug Discovery; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutation, Missense; Nitriles; Parkinson Disease; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proteome; Pyrimidines; Pyrroles; Rats

2015