Synthesis of mizoribine prodrugs and their in vivo evaluation as immunosuppressive agents

Mizoribine is a well-known immunosuppressive drug, based on a nucleoside scaffold, that targets inosinemonophosphate dehydrogenase (IMPDH). In an effort to increase its in vivo efficacy, three different types of prodrugs (a phosphoramidate prodrug, a lipophilic ester derivative and an amino acid conjugate) were prepared. Screening of these prodrugs in a rapid whole blood assay revealed that the two ester-based mizoribine prodrugs potently inhibited interleukin 2 secretion. Moreover, these prodrugs were able to prolong graft survival, when evaluated in a mouse model of cardiac allograft transplantation. Strikingly, a combination therapy of these mizoribine prodrugs with tacrolimus had a synergistic in vivo effect.

Automated summary

Researchers prepared three different types of prodrugs of Mizoribine, and found that the ester derivatives effectively inhibited the secretion of specific immune molecules and prolonged graft survival. The combination therapy of these prodrugs with tacrolimus also showed a synergistic effect in vivo.