6bbu

Publication Abstract from PubMed

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 EPO and TPO signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). 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.

Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfo namide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.,Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, MItton-Fry MJ, Johnson TA, TenBrink RE, Arnold EP, Basak A, Heasley SE, Kwon S, Langille J, Parikh MD, Griffin SH, Casavant JM, Duclos BA, Fenwick AE, Harris TM, Han S, Caspers NL, Dowty ME, Yang X, Banker ME, Hegen M, Symanowicz PT, Li L, Wang L, Lin TH, Jussif J, Clark JD, Telliez JB, Robinson RP, Unwalla R J Med Chem. 2018 Jan 3. doi: 10.1021/acs.jmedchem.7b01598. PMID:29298069^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.