Synthesis and Bioactivation of Selective Estrogen Receptor Modulators (SERMs)

The metabolism of estrogens and selective estrogen receptor modulators (SERMs) to electrophilic metabolites (bioactivation) has been postulated as a contributing factor in the initiation and/or promotion of cancer in hormone-sensitive tissues. Extended use of the prototypical triphenylethylene SERM tamoxifen, for example, has been associated with an increased risk for endometrial cancer. Bioactivation of tamoxifen to an electrophilic carbocation which covalently modifies DNA represents one possible mechanism to account for this increased risk. Conversely, while the benzothiophene (BT) SERM raloxifene may also be bioactivated to a highly reactive electrophile, this metabolic pathway has not been associated with human toxicity. Such observations highlight important needs to 1) Examine potential routes for toxicity resulting from the bioactivation of newer-generation SERMs, and 2) Develop novel SERMs for which drug bioactivation is unlikely to result in toxicity. In the present study, the oxidative metabolism of three SERMs, LY2066948 (LY), lasofoxifene (LAS), and bazedoxifene (BAZ), was investigated under various in vitro conditions. All three SERMs were found to be enzymatically oxidized to electrophilic o-quinones. For LY and BAZ, o-quinone formation represented a relatively minor metabolic pathway. Interestingly, for the case of LAS, o-quinone formation constituted the primary route of oxidative metabolism. Moreover, LAS o-quinone was found to generate covalent adducts with DNA, suggesting a potential mechanism for toxicity analogous to that of the structurally similar estrogen, estradiol. Importantly, while LY is an investigational SERM in preclinical development as a potential treatment for uterine fibroids, both BAZ and LAS are currently approved for use in the European Union as treatments for postmenopausal osteoporosis. The second major goal of the study was to design and synthesize novel SERMs based upon molecular scaffolds for which bioactivation is not associated with toxicity. As the BT core moiety present in raloxifene best met this criterion, this scaffold was deemed an ideal choice. Structural elaboration of this core led to discovery of a novel drug candidate for the treatment of tamoxifen-resistant breast cancer which maintained the antitumorigenic activity of alternative treatments, while displaying reduced toxicity in vivo. Collectively, the results of this study will provide valuable information in the design of new SERMs which maintain efficacy while minimizing toxicity associated with bioactivation.