title: Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.
abstract: By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Peter
authors.identifier: 0000-0001-8637-9530
authors.initials: P
authors.lastname: Jones
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sabnis
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Wakenhut
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: England
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Takasuke
authors.initials: T
authors.lastname: Mukaiyama
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Jotham W
authors.initials: JW
authors.lastname: Coe
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Steve W
authors.initials: SW
authors.lastname: Kortum
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Chrencik
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: David G
authors.initials: DG
authors.lastname: Brown
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Rhys M
authors.initials: RM
authors.lastname: Jones
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: John R
authors.initials: JR
authors.lastname: Murphy
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Thean
authors.initials: T
authors.lastname: Yeoh
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.affiliation: Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.|Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
authors.forename: Iain
authors.initials: I
authors.lastname: Kilty
mesh_terms: D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D022781:Hepatocytes / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008171:Lung Diseases / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012871:Skin Diseases / Q000188:drug therapy*; D012995:Solubility
chemical_list: D000893:Anti-Inflammatory Agents; D006574:Heterocyclic Compounds, 2-Ring; D007191:Indazoles; C000620977:PF-06263276; D047428:Protein Kinase Inhibitors; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053612:Janus Kinases