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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.
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 [J Med Chem] 2018 Feb 08; Vol. 61 (3), pp. 1130-1152. Date of Electronic Publication: 2018 Jan 23. - Publication Year :
- 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 :
- Animals
Arthritis, Experimental drug therapy
Cyclobutanes chemistry
Cyclobutanes pharmacokinetics
Cyclobutanes therapeutic use
Dogs
Drug Evaluation, Preclinical
Humans
Inhibitory Concentration 50
Janus Kinase 1 chemistry
Janus Kinase 2 antagonists & inhibitors
Models, Molecular
Protein Conformation
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacokinetics
Protein Kinase Inhibitors therapeutic use
Pyrimidines chemistry
Pyrimidines pharmacokinetics
Pyrimidines therapeutic use
Pyrroles chemistry
Pyrroles pharmacokinetics
Pyrroles therapeutic use
Rats
Substrate Specificity
Sulfonamides chemistry
Sulfonamides pharmacokinetics
Sulfonamides therapeutic use
Tissue Distribution
Autoimmune Diseases drug therapy
Cyclobutanes pharmacology
Janus Kinase 1 antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Pyrroles pharmacology
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29298069
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01598