Design Jak3 Kinase Inhibitor CP690550 Its Derivatives, Synthesis And Screening

Organ transplantation has been one of the greatest wonders in the field of medical science in the 20th century that thousands of organ failure patients have benefited from. Unfortunately, patients received transplanted organs require lifelong immunosuppression to various rejection of foreign organs. Thus, development of immunosuppressive drugs is the key to successful allograft fuction.The current immunosuppressive drugs used are mainly CsA、FK506、Rapamycin、FTY720 and so on, however, these immunosuppressive drugs lead to numerous and severe side effects such as nephrotoxicity、hypertension、anemia.Janus Kinase （Jak） 3, 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 TB⁺NK^- cell phenotype, named severe-combined immunodeficiency disease （SCID） that would be a novel target of small-molecular immunosuppressive drugs. Current reported specific inhibitors of Jak3 are WHI-P131、AG-490、PNU156804、CP690550 and so on. Compared to others, CP690550 shows the best inhibitory potency(IC₅₀) of 1nmol·L^-1. According to the principle of bioisosterism, on the basis of the structure of lead compound CP690550, using the program AUTODOCK3.0 to estimate the Free Energy of Binding between the compounds and ligand, we designed two sets of inhibitors of Jak3We synthesized CP690550（two chiral centers, 17 steps）, 2 derivatives with single configuration, 5 derivatives with cis-enantiomers and 20 derivatives with diastereomers whose structures were justified with NMR and MS methods, and we have optimized the synthesis methods of CP690550 and its derivatives.The results of in vitro assay indicated that CP690550 and its derivatives FYP07 and FYP15 had the similar inhibition rate in a concentration of 0.1μmol·L^-1 and 7 derivatives （chiralFYP28、cisFYP24、cisFYP25、cisFYP34、FYP17、FYP12、FYP11） showed a little inhibition in a concentration of 1μmol·L^-1. The next screening is ongoing.