title: Kinase domain inhibition of leucine rich repeat kinase 2 (LRRK2) using a [1,2,4]triazolo[4,3-b]pyridazine scaffold.
abstract: Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States. Electronic address: paul.galatsis@pfizer.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Henderson
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Kormos
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.affiliation: Primary Pharmacology Group, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Noell
authors.affiliation: Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Elie
authors.initials: E
authors.lastname: Needle
authors.affiliation: Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Drug Safety R&D, Pfizer Worldwide R&D, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Houle
authors.affiliation: Neuroscience Research Unit, Pfizer Worldwide R&D, 610 Main St., Cambridge, MA 02139, United States.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Kinase inhibitors; LRRK2; Leucine rich repeat kinase 2; Triazolopyridazine