TOXI 83 |
| The selective estrogen receptor modulators (SERMs), raloxifene and arzoxifene, are benzothiophene SERMs of clinical use in osteoporosis and breast cancer chemoprevention. Both raloxifene and DMA, the active metabolite of arzoxifene, are metabolized to electrophilic diquinone methides that are potentially toxic, electrophilic metabolites. The arzoxifene analogue, 4'F-DMA, has been shown to have similar antiestrogenic activity to DMA and raloxifene but with improved metabolic stability and attenuated formation of electrophilic metabolites. To further investigate structure-activity-bioactivation relationships in benzothiophene SERMs, a family of arzoxifene analogues was developed using an efficient novel synthetic route. Ligand binding to ERá and ERâ and activity in ERá-positive Ishikawa cells measured estrogenic or antiestrogenic activity. Metabolism and bioactivation was measured in rat liver microsomal incubations in the presence of GSH, in incubations with mushroom tyrosinase in the presence of GSH, and in human intestinal microsomes in the presence of UDPGA. The resulting data demonstrated a broad variety of oxidative chemistry, bioactivation, and metabolism profiles. These data show clearly that the development of benzothiophene SERMs with significantly attenuated bioactivation properties whilst maintaining antiestrogenic activity can be effected by minor structural modifications.
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Poster Presentations and Awards
6:00 PM-10:00 PM, Tuesday, 12 September 2006 Moscone Center -- Room 104, Poster
Sci-Mix
Division of Chemical Toxicology |