Pyrrolo[2,3]pyrimidine inhibitors of Janus kinase 3 protein tyrosine kinase

Abstract

Therapeutic immunosuppression (TI) remains vital for prevention of chronic rejection of transplanted organs or tissues. TI is typically maintained with combinations of calcineurin inhibitors (cyclosporin A), mammalian target of rapamycin (mTOR) inhibitors, inhibitors of inosine monophosphate dehydrogenase (IMPDH) (inhibited by mycophenolic acid) and antibodies specific for activated T lymphocytes (daclizumab). However, the adverse events associated with these agents limits their use in the treatment of severe, but not immediately life threatening, autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. Calcineurin, mTOR and IMPDH are ubiquitously expressed and some of the adverse events associated with their inhibition may be due to action outside the immune system. Janus kinase 3 (JAK3) is a protein tyrosine kinase whose expression is largely restricted to haematopoietic cells and humans deficient in JAK3 are immunocompromised but without other disorders. Pfizer presents a new class of JAK3 inhibitors and a method for chiral resolution of a precursor in their synthesis.

• autoimmunity
• immunosuppression
• Janus kinase (JAK)
• pyrrolopyrimidine
• tyrosine kinase inhibitor