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Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis

By Steven H. Spergel (2277832), Michael E. Mertzman (6326258), James Kempson (1665415), Junqing Guo (336321), Sylwia Stachura (6326261), Lauren Haque (2864195), Jonathan S. Lippy (2238256), Rosemary F. Zhang (6326264), Michael Galella (2038312), Sidney Pitt (2459557), Guoxiang Shen (2102542), Aberra Fura (1436362), Kathleen Gillooly (2381536), Kim W. McIntyre (1429864), Vicky Tang (6326267), John Tokarski (2415049), John S. Sack (2375029), Javed Khan (219271), Percy H. Carter (1355331), Joel C. Barrish (1429858), Steven G. Nadler (2123188), Luisa M. Salter-Cid (3228231), Gary L. Schieven (2459572), Stephen T. Wrobleski (2459575) and William J. Pitts (1665418)


The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib <b>1</b>, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound <b>22</b> was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug <b>32</b> enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA

Topics: Biochemistry, Medicine, Genetics, Molecular Biology, Physiology, Ecology, Sociology, Immunology, Cancer, Infectious Diseases, Chemical Sciences not elsewhere classified, Janus family, JAK 3., phosphate prodrug 32, JAK inhibitors, JAK family kinase inhibitor, nonreceptor tyrosine kinases, RA, JAK family selectivity profiles, Rheumatoid Arthritis, phosphate prodrugs, United States, CIA model, JAK 1, Demonstrate Efficacy, selectivity profile, tofacitinib 1, murine collagen
Year: 2019
DOI identifier: 10.1021/acsmedchemlett.8b00508.s001
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Provided by: FigShare
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