CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) 
molecules. The molecular pathways through which the JAK moieties function are 
described along with the clinical mechanisms associated with their inhibition. 
Animal models of JAK inhibition are reviewed as a background for the possible 
inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is 
described, and the Phase IIA and IIB trials are reviewed in some detail. These 
trials were dose-ranging and showed a general dose response with relatively 
robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 
6-week trial in which CP-690,550 was given as monotherapy was associated with 
highly efficacious responses at the mid and higher twice-daily dose ranges 
employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was 
administered in combination with methotrexate showed ACR20 responses, which were 
also statistically significant versus placebo interventions. CP-690,550 
treatment was associated with side effects, which included headache and nausea. 
Infections were more common versus placebo as were elevations in transaminase 
enzymes when administered in combination with methotrexate, and increases in 
low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. 
Decreases in haemoglobin and white blood cell (WBC) counts were also observed 
along with small increases in serum creatinine. Occasional significant decreases 
of haemoglobin (>2 g dl(-1)) were observed, although decreases of WBC to less 
than 1000 per mm(3) were not seen. Plans for long-term follow-up of the 
described trials are described along with the features of five presently ongoing 
Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future 
directions include completion and publication of these trials along with study 
of JAK inhibition for other indications.