NOVEL BIOLOGICAL RESPONSE MODIFIERS DERIVED FROM THALIDOMIDE

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypn otic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of vari ous diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in the se diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha , a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in va rious diseases, including AIDS, tumors, rheumatoid arthritis and diabe tes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide o n TNF-alpha. production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thal idomide possesses both enhancing and inhibiting activities on TNF-alph a production. Structural modification of thalidomide aiming at the cre ation of superior TNF-alpha production-regulate rs has afforded a numb er of phenyl- and benzylphthalimide analogs possessing more potent act ivity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha prod uction-regulating activity is electronic state-and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production ha s been obtained. Further structural development of the phthalimide ana logs has yielded potent non-steroidal androgen antagonists.