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

Spergel, Steven H.; Mertzman, Michael E.; Kempson, James; Guo, Junqing; Stachura, Sylwia; Haque, Lauren; Lippy, Jonathan S.; Zhang, Rosemary F.; Galella, Michael; Pitt, Sidney; Shen, Guoxiang; Fura, Aberra; Gillooly, Kathleen; McIntyre, Kim W.; Tang, Vicky; Tokarski, John; Sack, John S.; Khan, Javed; Carter, Percy H.; Barrish, Joel C.; Nadler, Steven G.; Salter-Cid, Luisa M.; Schieven, Gary L.; Wrobleski, Stephen T.; Pitts, William J.

doi:10.1021/acsmedchemlett.8b00508.s001

ml8b00508_si_001.pdf (489.54 kB)

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

journal contribution

posted on 2019-02-12, 22:14 authored by Steven H. Spergel, Michael E. Mertzman, James Kempson, Junqing Guo, Sylwia Stachura, Lauren Haque, Jonathan S. Lippy, Rosemary F. Zhang, Michael Galella, Sidney Pitt, Guoxiang Shen, Aberra Fura, Kathleen Gillooly, Kim W. McIntyre, Vicky Tang, John Tokarski, John S. Sack, Javed Khan, Percy H. Carter, Joel C. Barrish, Steven G. Nadler, Luisa M. Salter-Cid, Gary L. Schieven, Stephen T. Wrobleski, William J. Pitts

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, 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 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 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.