RATIONAL DESIGN OF NOVEL IMMUNOSUPPRESSIVE DRUGS - ANALOGS OF AZATHIOPRINE LACKING THE 6-MERCAPTOPURINE SUBSTITUENT RETAIN OR HAVE ENHANCEDIMMUNOSUPPRESSIVE EFFECTS

Clinical use of the immunosuppressive drug azathioprine is limited by potentially serious toxic effects related to depression of bone marrow function. The immunosuppressive and toxic properties of azathioprine are regarded as being properties of the cytotoxicity of its metabolite , 6-mercaptopurine (6-MP). However, azathioprine has an immunosuppress ive effect additional to that attributable to 6-MP alone, and we propo se that this is associated with an action of the methylnitroimidazolyl substituent. This suggests a route to the rational design of nontoxic immunosuppressants by replacing the 6-MP component of azathioprine wi th nontoxic thiols. We have synthesized and tested in vitro 24 such an alogues, with two being further tested in vivo. In the human mixed lym phocyte reaction, virtually all compounds showed some degree of activi ty, 10 compounds being more active than azathioprine. In vivo, two com pounds were more effective than azathioprine at prolonging graft survi val in mice. In an oral toxicity study in male CD1 mice at doses equiv alent to those at which azathioprine caused severe bone marrow depress ion both analogues had no toxic effects. Our results show that the imm unosuppressive effects and bone marrow toxicity of azathioprine are no t a consequence of release of 6-MP alone, and with appropriate modific ation can be separated, an approach which may lead to less toxic immun osuppressive drugs.