2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jan 26;60(2):767-786. doi: 10.1021/acs.jmedchem.6b01634.
Peter Jones 1 2 3,  R Ian Storer 1 2 3,  Yogesh A Sabnis 1 2 3,  Florian M Wakenhut 1 2 3,  Gavin A Whitlock 1 2 3,  Katherine S England 1 2 3,  Takasuke Mukaiyama 1 2 3,  Christoph M Dehnhardt 1 2 3,  Jotham W Coe 1 2 3,  Steve W Kortum 1 2 3,  Jill E Chrencik 1 2 3,  David G Brown 1 2 3,  Rhys M Jones 1 2 3,  John R Murphy 1 2 3,  Thean Yeoh 1 2 3,  Paul Morgan 1 2 3,  Iain Kilty 1 2 3
Affiliations

Affiliations

  • 1 Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 2 Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.
  • 3 Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K.
PMID: 27983835 DOI: 10.1021/acs.jmedchem.6b01634
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.

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