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-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene alpha to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement 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 toxicological profile, 60e was selected as a candidate for clinical evaluation.
Lebreton
L
L
Laboratoires Fournier S.A., Axe Immunologie, 50 Rue de Dijon, 21121 Daix, France.
Jost
E
E
Carboni
B
B
Annat
J
J
Vaultier
M
M
Dutartre
P
P
Renaut
P
P
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000188:drug therapy; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D013095:Spermidine / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous
C401320:2-((6-((aminoiminomethyl)amino)hexyl)amino)-2-oxoethyl (4-((3-aminobutyl)amino)butyl)carbamate; D002219:Carbamates; D006146:Guanidines; D007166:Immunosuppressive Agents; D013095:Spermidine; C037258:gusperimus