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

被引：1

作者：

Gao, Ling-Jie ^{[1
]}

Lin, Yuan ^{[2
]}

De Jonghe, Steven ^{[3
]}

Waer, Mark ^{[2
]}

Herdewijn, Piet ^{[1
]}

机构：

[1] Katholieke Univ Leuven, Rega Inst Med Res, Dept Pharmaceut & Pharmacol Sci, Lab Med Chem, Herestr 49,Box 1030, B-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Rega Inst Med Res, Lab Mol Immunol, Herestr 49,Box 1042, B-3000 Leuven, Belgium

[3] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol Immunol & Transplantat, Lab Virol & Chemotherapy, Herestr 49,Box 1043, B-3000 Leuven, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2023年 / 95卷

关键词：

Mizoribine; Prodrugs; Immunosuppressive agents; Inosine-monophosphate dehydrogenase; INOSINE MONOPHOSPHATE DEHYDROGENASE; NUCLEOSIDE; INHIBITORS; ANALOGS; IMPDH;

D O I：

10.1016/j.bmcl.2023.129490

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：5

共 21 条

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