title: Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free-Energy Perturbation (FEP).
abstract: There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative to the parent compound and no increase in atom count. Optimization of 17 led to compounds with nanomolar cellular activity.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA. frank.lovering@pfizer.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Lovering
authors.affiliation: Inflammation and Immunity, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aevazelis
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Chang
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehnhardt
authors.affiliation: Inflammation and Immunity, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Fitz
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Janz
authors.affiliation: Inflammation and Immunity, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Neelu
authors.initials: N
authors.lastname: Kaila
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonald
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: William
authors.initials: W
authors.lastname: Moore
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretto
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papaioannou
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Richard
authors.affiliation: Inflammation and Immunity, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Ryan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Wan
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, MA, 02139, USA.
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013816:Thermodynamics; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D014227:Triazines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: drug discovery; free-energy perturbation; imidazotriazines; molecular modeling; spleen tyrosine kinase