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
  • 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.
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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