A TACROLIMUS-RELATED IMMUNOSUPPRESSANT WITH REDUCED TOXICITY

Background. Tacrolimus (FR506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 bindin g protein-la, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe a dverse effects, including neurotoxicity and nephrotoxicity, Although t his toxicity, Like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry ef fort has been devoted to search for tacrolimus analogs with reduced to xicity but preserved immunosuppressive activity that might have enhanc ed therapeutic utility. Methods. Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (AS C), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-AS C was characterized in rodent models of immunosuppression and toxicity . Results. Indolyl-ASC was found to exhibit an immunosuppressive poten cy equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 ti mes less to intracellular FK506 binding protein-12 than tacrolimus or ASC, Further evaluation of indolyl-ASC revealed that it is threefold l ess potent than tacrolimus in inducing hypothermia, a response that ma y reflect neurotoxicity, and in causing gastrointestinal transit alter ations in mice, Moreover, indolyl-ASC was at least twofold less nephro toxic than tacrolimus upon 3-week oral treatment in rats. Conclusions. Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rode nt models.