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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, Journal Name: Journal of Medicinal Chemistry Journal Issue: 3 Vol. 61; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (44)

Profound Methyl Effects in Drug Discovery and a Call for New CH Methylation Reactions journal October 2013
A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone journal March 2012
Signaling by IL-2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency journal October 1996
Intracellular signal pathways: Potential for therapies journal October 2009
Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction journal December 1973
Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans journal April 1993
Selective synthesis of sulfonylureas and carboxysulfamides a novel route to oxazolidinones. journal January 1983
Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses journal May 1998
Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2 journal December 2012
Identification of azabenzimidazoles as potent JAK1 selective inhibitors journal January 2016
Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors journal April 2016
Systematic Review of Tofacitinib: A New Drug for the Management of Rheumatoid Arthritis journal July 2014
Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design journal November 2012
JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease journal April 2012
Dissecting Specificity in the Janus Kinases: The Structures of JAK-Specific Inhibitors Complexed to the JAK1 and JAK2 Protein Tyrosine Kinase Domains journal March 2009
Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6 journal July 2010
ATP-Mediated Kinome Selectivity: The Missing Link in Understanding the Contribution of Individual JAK Kinase Isoforms to Cellular Signaling journal May 2014
Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis journal December 2007
Functional group contributions to drug-receptor interactions journal December 1984
Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection journal December 2010
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors journal June 2012
Identification of C -2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2 journal May 2013
Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases: Miniperspective journal January 2014
Mild and Safer Preparative Method for Nonsymmetrical Sulfamides via N -Sulfamoyloxazolidinone Derivatives:  Electronic Effects Affect the Transsulfamoylation Reactivity journal July 2006
An Improved and Efficient Process for the Preparation of Tofacitinib Citrate journal November 2014
Ruxolitinib journal February 2012
Regulation of JAK–STAT signalling in the immune system journal November 2003
STATs: transcriptional control and biological impact journal September 2002
Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases journal December 2015
Research applications of the Cambridge Structural Database (CSD) journal January 2004
JAK-STAT Signaling: From Interferons to Cytokines journal July 2007
Cytokines and their role in lymphoid development, differentiation and homeostasis journal January 2002
Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system journal October 2016
Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment journal October 2013
Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study journal March 2018
Janus kinases in immune cell signaling journal March 2009
Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis journal November 2013
Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor journal October 2003
Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate journal November 2014
Utility of animal models for identification of potential therapeutics for rheumatoid arthritis journal November 2007
JAKS AND STATS: Biological Implications journal April 1998
Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis journal January 2010
Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050 journal April 2010
Progress toward JAK1-selective inhibitors journal February 2015

Cited By (7)

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases journal January 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
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
Janus kinases to jakinibs: from basic insights to clinical practice journal February 2019
Emerging Topical and Systemic JAK Inhibitors in Dermatology journal December 2019

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Related Subjects

Assays
60 APPLIED LIFE SCIENCES
Ligands
Peptides and proteins
Selectivity
Sulfones