Design, Synthesis And Screening Of CP690550 And Janus Kinase 3 Inhibitors

Organ Transplantation is one of the greatest wonders in the field of medical science in the 20th century which have benefited thousands of organ failure patients. Unfortunately, patients received transplanted organs require lifelong immunosuppression to various rejection of foreign organs. Thus, the development of immunosuppressive drugs is the key to successful allograft function.The currently used immunosuppressive drugs are mainly CsA, FK506, Rapamycin, FTY720, and so on. However, these immunosuppressive drugs lead to numerous severe side effects such as nephrotoxicity, hypertension and anemia.Janus Kinase 3(Jak3), a protein tyrosine kinase, plays a crucial role in the Jak-STAT signal pathway of immuno-regulatory cytokine receptors with the common gamma chain. Jak3 inhibition is characterized by numerous developmental and functional immune-cell deficiencies resulting in a T^-B⁺NK^- cell phenotype, named severe-combined immunodeficiency disease(SCID) that would be a novel target of small-molecular immunosuppressive drugs. The specific inhibitors of Jak3 currently reported are WHI-P131,AG490,PNU156804,CP690550 and so on. Among which, CP690550 shows the best inhibitory potency(IC5o =1nmol·L^-1). According to the principle of bioisosterism, we designed new inhibitors of Jak3 by mimicing the structure of lead compound CP690550.CP690550 as well as its 9 optically active and 9 racemic analogs has been synthesized. The structure of all the desired compounds was determined by NMR and MS. The synthetic method of CP690550 was also impoved.The absolute configuration of (1-benzyl-4-methyl-piperidine-3-yl)-methylamine was determined by cultivating monocrystal and turned out to be (3R,4R). The enantiomer excess(ee) was 99.73%.The screening of in vitro assay is ongoing.