Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety

Abstract

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derivative 56h in which the pro-R hydrogen of the methylene alpha to the primary amine of the spermidine moiety has been replaced by a methyl group.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.

Induction of T Regulatory Cells Attenuates Idiopathic Nephrotic Syndrome

“…26 DSG has proved its efficiency in extending the survival of skin, heart, kidney, bone marrow, pancreatic islets, and liver transplantation in animals and humans and reverting rejection in human renal allotransplantation. 27 More recently, LF15-0195, a stabilized DSG derivative, was shown to produce a beneficial effect in graft-versus-host disease, 14 allotransplantation, 19,28 xenotransplantation, experimental autoimmune encephalomyelitis, myasthenia, arthritis, and anti-glomerular basement membrane glomerulonephri- Figure 5. Accumulation of transcripts for the regulatory markers CD25, CTLA4, GITR, IDO, and iNOS in LF15-0195-treated in comparison with untreated age-matched spleens.…”

“…Only a deoxyspergualin (DSG) derivative, LF15-0195, 14 specifically induced a rapid and complete remission of the initial kidney disease as well as its posttransplantation recurrence. This effect was manifested as a resolution of both proteinuria and histologic lesions.…”

LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level

“…6 Several analogs were obtained recently through organic synthesis. 7,8 One of these compounds, designated LF 15-0195, has demonstrated its efficacy in preventing graft-versus-host disease 8 and in treating collagen type II-induced arthritis 9,10 in mice models. Although LF 15-0195 is now tested in human clinics, the molecular mechanisms of its immunosuppressive activity differ from currently used immunosuppressive agents but remain poorly understood.…”

Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: A review on tacrolimus and cyclosporin in organ transplantation

“…Trials with the first of the new generation of primary immunosuppressants, tacrolimus (FK506) began six years later and were followed by a continually growing series of new agents. The most widely evaluated and promising currently are mycophenolic acid mofetil, sirolimus (rapamycin), mizorbine, deoxyspergualin, brequinar sodium, leflunomide and monoclonal antibody preparations (1,36,37).…”