SDZ RAD, A NEW RAPAMYCIN DERIVATIVE - PHARMACOLOGICAL PROPERTIES IN-VITRO AND IN-VIVO

Background. This report describes the preclinical pharmacological prof ile of the new rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)- rapamycin. Methods. The pharmacological effects of SDZ RAD were assess ed in a variety of in vitro and in vivo models, which included an auto immune disease model as well as kidney and heart allotransplantation m odels using different rat strain combinations. Results. SDZ RAD has a mode of action that is different from that of cyclosporine or FK506. I n contrast to the latter, SDZ RAD inhibits growth factor-driven cell p roliferation in general, as demonstrated for the in vitro cell prolife ration of a lymphoid cell line and of vascular smooth muscle cells, SD Z RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of an tigen-driven proliferation of human T-cell clones, The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when gi ven by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg /day. When compared with rapamycin, the in vitro activity of SDZ RAD i s generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as rapamycin. Conclusio ns. In conclusion, SDZ RAD is a new, orally active rapamycin-derivativ e that is immunosuppressive and that efficiently prevents graft reject ion in rat models of allotransplantation. SDZ RAD has therefore been s elected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantat ion.