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Title: Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Journal Article · · Journal of Medicinal Chemistry
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  1. Pfizer Inc, Cambridge, MA (United States)
  2. Pfizer Inc, Groton, CT (United States)
  3. Pfizer Inc, Kalamazoo, MI (United States)
  4. Pfizer Inc, Chesterfield, MO (United States)
  5. Pfizer Inc, Andover, MA (United States)
+ Show Author Affiliations

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. We report improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1526050
Journal Information:
Journal of Medicinal Chemistry, Vol. 61, Issue 3; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 76 works
Citation information provided by
Web of Science

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Cited By (7)

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs journal July 2018
JAK Inhibitors for Atopic Dermatitis: An Update journal December 2018
Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases journal January 2019
Janus kinases to jakinibs: from basic insights to clinical practice journal February 2019
Emerging Topical and Systemic JAK Inhibitors in Dermatology journal December 2019
Emerging Topical and Systemic JAK Inhibitors in Dermatology text January 2019
On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition journal November 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
Peptides and proteins
Ligands
Assays
Sulfones
Selectivity