title: Novel biological response modifiers derived from thalidomide.
abstract: Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity.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 various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these 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 various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007917:Leprostatic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D000726:Androgen Antagonists; D019380:Anti-HIV Agents; D006993:Hypnotics and Sedatives; D007166:Immunosuppressive Agents; D007917:Leprostatic Agents; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide