Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

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.

At present, the methods and enzymology of the UDP-glucuronosyltransferases (UGTs) lag behind that of the cytochromes P450 (CYPs). About 15 human UGTs have been identified, and knowledge about their regulation, substrate selectivity, and tissue distribution has progressed recently. Alamethicin has been characterized as a treatment to remove the latency of microsomal glucuronidations. Most UGT isoforms appear to have a distinct hepatic and/or extrahepatic expression, resulting in significant expression in kidney, intestine, and steroid target tissues. The gastrointestinal tract possesses a complex expression pattern largely containing members of the UGT1A subfamily. Thus, these forms are poised to participate in the first pass metabolism of oral drugs. The authors and others have identified a significant expression of UGT1A1 in human small intestine, an enzyme possessing considerable allelic variability and a polymorphic expression pattern in intestine. Intestinal glucuronidation therefore plays a major role not only in first pass metabolism, but also in the degree of interindividual variation in overall oral bioavailability. Due to issues such as significant genetic variability and tissue localization in first-pass organs, clearance due to UGT1A1 should be minimized for new drugs.

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