Immunomodulatory activity of malononitrilamides, derivatives of leflunomide’s primary metabolite, on models of experimental rheumatoid arthritis

Autor: H.U Schorlemmer, R Schleyerbach, R.R Bartlett
Rok vydání: 1998
Předmět:
Zdroj: Transplantation Proceedings. 30:4137-4139
ISSN: 0041-1345
Popis: HE ISOXAZOL derivative leflunomide has been found to demonstrate profound immunosuppressive activity, and to be effective in the prevention and treatment of an array of animal models for autoimmune diseases and in the suppression of allo- and xenograft rejection 1 by reducing disease-specific antibody formation. Recent data from a Phase II and current Phase III clinical trials show leflunomide to be safe and effective in the treatment of patients with active rheumatoid arthritis. Malononitrilamides (MNAs) represent a new generation of low-molecular-weight immunosuppressive agents and belong to the analogues of the main metabolite of leflunomide A77 1726. They share no apparent structural relationship with the existing immunosuppressive drugs and early in vitro studies revealed that the mechanism of immunosuppression is similar to the parent compound. The malononitrilamides HMR 1279 (C14H11N3O2, with a molecular weight of 253,26) and HMR 1715 (C15H11F3N2O2, with a molecular weight of 308,26) mediate their immunosuppressive effects primarily by specifically binding to dihydro-orotate-dehydrogenase (DHODH) and blocking the fourth enzyme of the de novo pyrimidine biosynthesis pathway. 2,3 These derivatives of leflunomide’s active metabolite A77 1726 have been reported to inhibit the cellular and humoral immune responses in vitro. They were found to suppress the proliferation of several immune and non-immune cells 4,5 and were potent inhibitors of the IgM and IgG antibody response, 6 primarily reducing auto-, allo-, and xenoantibody formation. Both MNAs were very effective when tested in rodent transplantation models, where they were shown to prevent and reverse acute allograft rejection in mice and rats 7‐11 and control hamster-to-rat or mouse-to-rat xenograft survival, 8,12‐15 while being well tolerated in these experiments. They also effectively controlled graft-versushost diseases (GvHD) in various rodent models. 16 ‐20 Recently, HMR 1279 and HMR 1715 have been reported as effective inhibitors of T- and B-cell mediated autoimmune processes against a variety of rodent models for experimental autoimmune diseases. 21‐25 Based on the promising results obtained thus far in the various autoimmune disease models, we further elucidate herein the disease-modifying potential of the MNAs in models of chronic degenerative joint disease of adjuvant arthritis (AA) in Lewis rats and the spontaneous developing polyarthritis in MRL/lpr-lpr autoimmune mice.
Databáze: OpenAIRE
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