Ethamoxytriphetol

Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen (that is, a silent antagonist of the estrogen receptor (ER)) but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however. MER-25 produces antifertility effects in animals, and garnered interest as a potential hormonal contraceptive. However, clinical development was discontinued due to its low potency and the incidence of unacceptable central nervous system side effects, including hallucinations and psychotic episodes, with higher doses. Undesirable gastrointestinal side effects were also described. Prior to being discontinued, the drug was also administered by Roy Hertz to three patients with metastatic breast cancer and was found to provide relief from bone pain, presumably due to dissolution of bone metastases. This was the first such study of its kind of antiestrogen therapy for the treatment of breast cancer, and it led to the development of tamoxifen for this indication a decade later. The drug was also evaluated for the purpose of ovulation induction and as a treatment of chronic mastitis and endometrial cancer before clinical development was stopped. MER-25, a simple triphenylethanol derivative, is closely related structurally to the triphenylethylene (TPE) group of SERMs, which includes clomifene and tamoxifen. The drug, a derivative of the cholesterol-lowering agent triparanol (MER-29) (which itself was derived from the estrogen chlorotrianisene (also known as TACE)), was originally being studied in animals at Merrell Dow as a treatment for coronary artery disease.