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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
- Source :
- Journal of Medicinal Chemistry. 61:1130-1152
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
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.
- 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
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....73b9d013c1aa57b2199cce24ad33fac0