SERMs: evolutionary chemistry, revolutionary biology

Estrogens are known as important modulators of development, growth and maintenance of primary sexual physiology. The medical field has also grown increasingly appreciative of the effects of estrogens on non-traditional target tissues such as bone, cardiovascular tissue and the CNS. Postmenopausal women have been the beneficiaries of estrogen supplementation regimes, but the proliferative actions of estrogens on uterine and breast tissue have raised concerns. Combining estrogens with progestins (HRT) has succeeded in blunting the uterine effects of estrogen but not the effects of estrogens on breast tissue, and breakthrough bleeding induced by HRT regimes continues to present compliance issues. The discovery by Jordan and coworkers in 1987 that the "antiestrogens" tamoxifen and raloxifene showed estrogenic effects in preventing bone loss in ovariectomized rats revolutionized the way we have come to the think of nuclear receptor functioning. Since that time, broad insights have been garnered into both the mechanisms involved in the primary, ligand activated nuclear transcription pathway as well as other, non-traditional pathways via which estrogens may exert their effects. The recent discovery of a second estrogen receptor ERbeta has provided additional possibilities for investigation and therapeutic intervention. Even though raloxifene (Evista) has been approved for the treatment and prevention of osteoporosis in postmenopausal women, there is room for improvement. For example, normal HRT alleviates hot flush and urogenital complaints; raloxifene does neither. In addition raloxifene does not raise overall HDL (while HRT does) but does increase venous thromboembolisms. The ideal SERM will maximize all of the positive estrogen attributes while minimizing the negatives, and to that end, there has been considerable activity in the medicinal chemistry community dedicated towards the modification of the SERM structure to achieve compounds with preferable profiles. What we have witnessed, so far, is an evolutionary march of compounds with potential clinical benefit over raloxifene, although the ideal SERM remains to be realized.