Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 2. Structural modifications of the spermidine moiety

A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versu s-host disease (GVHD) model in mice. Various substitutions of the spermidin e "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation we re first investigated leading to the discovery of the monomethylated maloni c derivative 56h in which the pro-R hydrogen of the methylene a to the prim ary amine of the spermidine moiety has been replaced by a methyl group. Syn thesis of the similarly methylated analogue of the previously reported glyc olic derivative LF 08-0299 afforded 60e which demonstrated a powerful activ ity at a dose as low as 0.3 mg/kg in the GVHD model and was much more poten t than DSG in the demanding heart allotransplantation model in rats. The im provement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicologic al profile, 60e was selected as a candidate for clinical evaluation.