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

  • Bioorg Med Chem Lett. 2023 Oct 15:95:129490. doi: 10.1016/j.bmcl.2023.129490.
Ling-Jie Gao  1 ,  Yuan Lin  2 ,  Steven De Jonghe  3 ,  Mark Waer  2 ,  Piet Herdewijn  4
Affiliations
  • 1. KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, Box 1030, 3000 Leuven, Belgium.
  • 2. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Herestraat 49, Box 1042, 3000 Leuven, Belgium.
  • 3. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • 4. KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, Box 1030, 3000 Leuven, Belgium. Electronic address: [email protected].
PMID: 37770001 DOI: 10.1016/j.bmcl.2023.129490
Abstract

Mizoribine is a well-known immunosuppressive drug, based on a nucleoside scaffold, that targets inosine-monophosphate 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.

Keywords
Immunosuppressive agents; Inosine-monophosphate dehydrogenase; Mizoribine; Prodrugs.
Products