There is a critical need for safer and more convenient treatments for organ 
transplant rejection and autoimmune disorders such as rheumatoid arthritis. 
Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are 
involved in the signaling of multiple cytokines important for various T cell 
functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was 
anticipated to provide therapeutic immunosuppression/immunomodulation. The 
Pfizer compound library was screened against the catalytic domain of JAK3 
resulting in the identification of a pyrrolopyrimidine-based series of 
inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were 
screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast 
proliferation assay. Select compounds were evaluated in rodent efficacy models 
of allograft rejection and destructive inflammatory arthritis. Optimization 
within this chemical series led to identification of CP-690,550 1, a potential 
first-in-class JAK inhibitor for treatment of autoimmune diseases and organ 
transplant rejection.