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

Jaclyn L Henderson; Bethany L Kormos; Matthew M Hayward; Karen J Coffman; Jayasankar Jasti; Ravi G Kurumbail; Travis T Wager; Patrick R Verhoest; G Stephen Noell; Yi Chen; Elie Needle; Zdenek Berger; Stefanus J Steyn; Christopher Houle; Warren D Hirst; Paul Galatsis

doi:10.1021/jm5014055

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

J Med Chem. 2015 Jan 8;58(1):419-32. doi: 10.1021/jm5014055. Epub 2014 Nov 17.

Authors

Jaclyn L Henderson¹, Bethany L Kormos, Matthew M Hayward, Karen J Coffman, Jayasankar Jasti, Ravi G Kurumbail, Travis T Wager, Patrick R Verhoest, G Stephen Noell, Yi Chen, Elie Needle, Zdenek Berger, Stefanus J Steyn, Christopher Houle, Warren D Hirst, Paul Galatsis

Affiliation

¹ Worldwide Medicinal Chemistry, ‡Neuroscience Research Unit, and §Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.

PMID: 25353650
DOI: 10.1021/jm5014055

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.

MeSH terms

Amino Acid Sequence
Animals
Area Under Curve
Brain / metabolism
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 / chemistry
Nitriles / pharmacokinetics
Nitriles / pharmacology*
Parkinson Disease / drug therapy
Protein Binding
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics
Protein Structure, Tertiary
Proteome / antagonists & inhibitors*
Proteome / chemistry
Proteome / metabolism
Pyrimidines / chemistry
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Pyrroles / chemistry
Pyrroles / pharmacokinetics
Pyrroles / pharmacology*
Rats

Substances

3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile
Nitriles
Protein Kinase Inhibitors
Proteome
Pyrimidines
Pyrroles
benzonitrile
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases

Associated data

PDB/4U8Z
PDB/4W8D
PDB/4W8E