title: 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.
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.
authors.affiliation: Worldwide Medicinal Chemistry, ‡Neuroscience Research Unit, and §Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Henderson
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Kormos
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hayward
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Coffman
authors.forename: Jayasankar
authors.initials: J
authors.lastname: Jasti
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Noell
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Elie
authors.initials: E
authors.lastname: Needle
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.forename: Christopher
authors.initials: C
authors.lastname: Houle
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020125:Mutation, Missense; D009570:Nitriles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: C000597233:3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011743:Pyrimidines; D011758:Pyrroles; C014356:benzonitrile; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases