| Literature DB >> 30891131 |
Steven H Spergel1, Michael E Mertzman1, James Kempson1, Junqing Guo1, Sylwia Stachura1, Lauren Haque1, Jonathan S Lippy1, Rosemary F Zhang1, Michael Galella1, Sidney Pitt1, Guoxiang Shen1, Aberra Fura1, Kathleen Gillooly1, Kim W McIntyre1, Vicky Tang1, John Tokarski1, John S Sack1, Javed Khan1, Percy H Carter1, Joel C Barrish1, Steven G Nadler1, Luisa M Salter-Cid1, Gary L Schieven1, Stephen T Wrobleski1, William J Pitts1.
Abstract
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.Entities:
Year: 2019 PMID： 30891131 PMCID： PMC6421541 DOI： 10.1021/acsmedchemlett.8b00508
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345