jm7b01598_si_001.pdf (1.41 MB)
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 contribution
posted on 2018-01-03, 00:00 authored by Michael
L. Vazquez, Neelu Kaila, Joseph W. Strohbach, John D. Trzupek, Matthew F. Brown, Mark E. Flanagan, Mark J. Mitton-Fry, Timothy A. Johnson, Ruth E. TenBrink, Eric P. Arnold, Arindrajit Basak, Steven E. Heasley, Soojin Kwon, Jonathan Langille, Mihir D. Parikh, Sarah H. Griffin, Jeffrey M. Casavant, Brian A. Duclos, Ashley E. Fenwick, Thomas M. Harris, Seungil Han, Nicole Caspers, Martin E. Dowty, Xin Yang, Mary Ellen Banker, Martin Hegen, Peter T. Symanowicz, Li Li, Lu Wang, Tsung H. Lin, Jason Jussif, James D. Clark, Jean-Baptiste Telliez, Ralph P. Robinson, Ray UnwallaJanus 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.
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JAK 1 pairsintracellular tyrosine kinasesJAK 1-selective inhibitorTYKSelective JAK 1 Clinical Candidateblood assaynanomolar potency3- aminopiperidine linkerPF -04965842pyrimidin -4-ylAutoimmune Diseases Janus kinasesJAK inhibitorJAK 1 inhibitorsJAK 2 homodimergrowth factorsJAK 1-mediatedrat adjuvant-induced arthritisJAK 1 potency
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