2. Academic Validation
  3. 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

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.
Jaclyn L Henderson 1,  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
Affiliations

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.

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