1. 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
- Author
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Seungil Han, Martin E. Dowty, Ralph P. Robinson, Steven E. Heasley, Peter T. Symanowicz, Jason Jussif, Thomas M. Harris, Neelu Kaila, Lu Wang, Matthew Frank Brown, Jeffrey M. Casavant, Nicole Caspers, Sarah H. Griffin, Mark J. Mitton-Fry, Martin Hegen, Johnson Timothy Allan, Tenbrink Ruth E, Mary Ellen Banker, Jonathan Langille, Mihir D. Parikh, Tsung H. Lin, Arindrajit Basak, Jean-Baptiste Telliez, James D. Clark, Strohbach Joseph Walter, Eric P. Arnold, Ray Unwalla, Li Li, Brian A. Duclos, Xin Yang, Mark Edward Flanagan, John David Trzupek, Michael L. Vazquez, Soojin Kwon, and Ashley Edward Fenwick
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Drug Evaluation, Preclinical ,Arthritis ,Inflammation ,Pharmacology ,Autoimmune Diseases ,Substrate Specificity ,Inhibitory Concentration 50 ,03 medical and health sciences ,Dogs ,Immune system ,Drug Discovery ,medicine ,Animals ,Humans ,Pyrroles ,Tissue Distribution ,Protein Kinase Inhibitors ,Thrombopoietin ,Sulfonamides ,Tofacitinib ,Chemistry ,Janus Kinase 1 ,Janus Kinase 2 ,medicine.disease ,Arthritis, Experimental ,Rats ,Pyrimidines ,030104 developmental biology ,Tyrosine kinase 2 ,Molecular Medicine ,medicine.symptom ,Janus kinase ,Tyrosine kinase ,Cyclobutanes - Abstract
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. 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.
- Published
- 2018