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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

Journal Article · · Journal of Medicinal Chemistry
ORCiD logo [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9];  [9];  [9];  [10];  [11];  [12];  [9];  [11];  [11]
  1. Pfizer Inc., Cambridge, MA (United States); Pfizer Ltd., Sandwich (United Kingdom)
  2. Pfizer Ltd., Sandwich (United Kingdom); AstraZeneca, Cambridge (United Kingdom)
  3. Pfizer Ltd., Sandwich (United Kingdom); UCB Pharma, Brussels (Belgium)
  4. Pfizer Ltd., Sandwich (United Kingdom); B. Braun Melsungen AG, Melsungen (Germany)
  5. Pfizer Ltd., Sandwich (United Kingdom); Sandexis Medicinal Chemistry Ltd, Kent (United Kingdom)
  6. Pfizer Ltd., Sandwich (United Kingdom); Univ. of Oxford (United Kingdom)
  7. Pfizer Ltd., Sandwich (United Kingdom); The Scripps Research Inst., La Jolla, CA (United States)
  8. Pfizer Inc., Cambridge, MA (United States); Xenon Pharmaceuticals, Burnaby, BC (Canada)
  9. Pfizer Inc., Groton, CT (United States)
  10. Pfizer Ltd., Sandwich (United Kingdom); Univ. of Kent (United Kingdom)
  11. Pfizer Inc., Cambridge, MA (United States)
  12. Pfizer Inc., Sandwich (United Kingdom)
+ Show Author Affiliations

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. Furthermore, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
Grant/Contract Number:
AC02-05CH11231; AC02-06CH11357; 085P1000817
OSTI ID:
1342254
Journal Information:
Journal of Medicinal Chemistry, Vol. 60, Issue 2; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 40 works
Citation information provided by
Web of Science

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Cited By (6)

One-step construction of complex polyheterocycles via a sequential post-GBB cyclization/spiro ring expansion triggered by a [1,5]-hydride shift journal January 2018
The natural polyphenol curcumin induces apoptosis by suppressing STAT3 signaling in esophageal squamous cell carcinoma journal December 2018
Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs journal July 2018
Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats journal May 2019
Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper journal January 2019
Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives journal October 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
hydrocarbons
amides
peptides and proteins
assays
inhibition