Novel Biological Response Modifiers Derived from Thalidomide

Title:Novel Biological Response Modifiers Derived from Thalidomide

Volume: 5 Issue: 3

Author(s): Yuichi Hashimoto

Affiliation:

Abstract: Thalidomide (N-α-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was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity.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-a (TNF-α) production. Because TNF-α, 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 TNFα production has been found to be bidirectional, depending on both the cell-type and the TNF-α production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-α production. Structural modification of thalidomide aiming at the creation of superior TNF-α 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-α production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-α production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.

Cite this article as:

Hashimoto Yuichi, Novel Biological Response Modifiers Derived from Thalidomide, Current Medicinal Chemistry 1998; 5 (3) . https://dx.doi.org/10.2174/0929867305666220314203435