The evolution of nonsteroidal antiestrogens to become selective estrogen receptor modulators

Abstract

The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding that ethamoxytriphetol was a "morning after" pill in laboratory animals, energized the pharmaceutical industry to discover more potent derivatives. In the wake of the enormous impact of the introduction of the oral contraceptive worldwide, contraceptive research was a central focus in the early 1960's. Numerous compounds were discovered e.g., clomiphene, nafoxidine, and tamoxifen, but the fact that clinical studies showed no contraceptive actions, but, in fact, induced ovulation, dampened enthusiasm for clinical development. Only clomiphene moved forward to pioneer an application to induce ovulation in subfertile women. The fact that all the compounds were antiestrogenic made an application in patients to treat estrogen responsive breast cancer, an obvious choice. However, toxicities and poor projected commercial returns severely retarded clinical development for two decades. In the 1970's a paradigm shift in the laboratory to advocate long term adjuvant tamoxifen treatment for early (non-metastatic) breast cancer changed medical care and dramatically increased survivorship. Tamoxifen pioneered that paradigm shift but it became the medicine of choice in a second paradigm shift for preventing breast cancer during the 1980's and 1990's. This was not surprising as it was the only medicine available and there was laboratory and clinical evidence for the eventual success of this application. Tamoxifen is the first medicine to be approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at high risk. But it was the re-evaluation of the toxicology of tamoxifen in the 1980's and the finding that there was both carcinogenic potential and a significant, but small, risk of endometrial cancer in postmenopausal women that led to a third paradigm shift to identify applications for selective estrogen receptor (ER) modulation. This idea was to establish a new group of medicines now called selective ER modulators (SERMs). Today there are 5 SERMs FDA approved (one other in Europe) for applications ranging from the reduction of breast cancer risk and osteoporosis to the reduction of menopausal hot flashes and improvements in dyspareunia and vaginal lubrication. This article charts the origins of the current path for progress in women's health with SERMs.

Keywords: Breast cancer; Endometrial cancer; Osteoporosis; Women’s health.

Fig. 1

Compounds described in the text.

Fig. 2

The inhibition of cholesterol biosynthesis by triparanol, clomiphene, tamoxifen, and the β-chlorinated derivative of tamoxifen toremifene.

Fig. 3

The pioneering bitransplantation study by Gottardis (72) with an ER-positive breast tumor (MCF-7) implanted in one axilla and an ER-positive endometrial tumor (EnCa 101) in the other axilla. Tamoxifen blocks estrogen-stimulated growth of the breast tumor (right), but tamoxifen encourages the growth of the endometrial tumor (left). These data were transmitted immediately to the clinical community (53, 54), confirmed in clinical trials (55, 56) to change clinical practice.

Fig. 4

The approvals of individual selective oestrogens receptor modulators (SERMs) in the United States of America through the evaluation system of the Food and Drug Administration (FDA). Approvals were specifically for indications at the highest level of toxicologic safety for women without disease but as a new hormone replacement therapy with conjugated estrogen (HRT+CE) to prevent disease ie: chemoprevention of osteoporosis, breast cancer (BC), menopausal symptoms or dyspareunia. One SERM, lasofoxifene, was approved for use in the European Union (EU) but was never launched or marketed despite the fact that clinical trials demonstrated a reduction in breast cancer (BC), osteoporosis fracture, strokes, endometrial cancer (EC) and coronary heart disease (CHD) (89).

Fig. 5

Origins of current selective ER modulators from earlier nonsteroidal antiestrogens. The discovery that the metabolite of tamoxifen, 4-hydroxytamoxifen (Fig. 1) has a very high binding affinity for the ER (15) acted as a catalyst for the design of the majority of future SERMs. The raloxifene drug development “odyssey” throughout the 1980’s (97) is a replay of the tamoxifen tale (71). During the 70’s (71), interestingly enough the work was done in the same laboratory but on different continents! The repurposing (92) and repatenting (97) of a failed breast cancer drug (keoxifene) resulted in raloxifene (Fig. 1), the same SERM, to establish a principle in translational research. Bazedoxifene is an adaptation of an estrogenic metabolite from a failed breast cancer drug Zindoxifene (85). Ospemifene is a known metabolite of the breast cancer drug toremifene. The metabolite of toremifene was found because an analogous metabolite Y was discovered for tamoxifen in the early 1980’s (88). Lasofoxifene has its origins with failed antifertility agent discovered in the early 1960’s U-11, 100A (8). The compound renamed nafoxidine was tested as a drug for the treatment of breast cancer but again failed because of serious side effects (9).

Fig. 6

Progress toward an ideal SERM. The overall good or bad aspects of administering hormone replacement therapy (HRT) to postmenopausal women compared with the observed site-specific actions of the SERMs tamoxifen and raloxifene. The known beneficial or negative actions of SERMs have opened the door for drug discovery to create the ideal SERM or targeted SERMs to either improve quality of life or prevent diseases associated with aging in women. This figure is published with permission from Elsevier. Jordan, V.C. Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell, 2004 Mar; 5(3): 207–213.