Ethamoxytriphetol (developmental code name MER-25) is a synthetic

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mod ...

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or ...

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 The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...

have been observed, so it is not a pure antiestrogen (that is, a

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

(ER)) but is, instead, technically a

selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists a ...

(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 Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...

. However, clinical development was discontinued due to its low

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...

and the incidence of unacceptable

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s, including

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

s and

psychotic episode Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior t ...

s, with higher doses. Undesirable

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

side effects were also described. Prior to being discontinued, the drug was also administered by Roy Hertz to three patients with

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

and was found to provide relief from

bone pain Bone pain (also known medically by several other names) is pain coming from a bone, and is caused by damaging stimuli. It occurs as a result of a wide range of diseases or physical conditions or both, and may severely impair the quality of life. ...

, presumably due to dissolution of

bone metastases Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that results from primary tumor invasion to bone. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare; the most common ...

. 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 Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

for this indication a decade later. The drug was also evaluated for the purpose of

ovulation induction Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles Ovulation Induction Retrieved on Mars 7, 2010 to reverse anovulation or oligoovulation. S ...

and as a treatment of chronic

mastitis Mastitis is inflammation of the breast or udder, usually associated with breastfeeding. Symptoms typically include local pain and redness. There is often an associated fever and general soreness. Onset is typically fairly rapid and usually occurs ...

and

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...

before clinical development was stopped. MER-25, a simple

triphenylethanol Triphenylethanol, or 1,1,2-triphenylethanol, is an organic compound with a condensed structural formula of , and is related to triphenylethylene, from which it can be prepared by hydration. It is the structural analog of two drugs, the never-marke ...

derivative, is closely related structurally to the

triphenylethylene Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is ...

(TPE) group of SERMs, which includes

clomifene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...

and tamoxifen. The drug, a derivative of the

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

-lowering agent

triparanol Triparanol (, ; brand name and development code MER/29, as well as many other brand names) was the first synthetic cholesterol-lowering drug. It was patented in 1959 and introduced in the United States in 1960. The developmental code name of trip ...

(MER-29) (which itself was derived from the estrogen

chlorotrianisene Chlorotrianisene (CTA), also known as tri-''p''-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal ...

(also known as TACE)), was originally being studied in animals at

Merrell Dow Marion Merrell Dow and its predecessor Marion Laboratories was a U.S. pharmaceutical company based in Kansas City, Missouri from 1950 until 1996. The company specialized in bringing to market drugs that had been discovered but unmarketed by other ...

as a treatment for

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

. Its antiestrogenic properties were discovered serendipitously when Leonard Lerner, a

research Research is "creativity, creative and systematic work undertaken to increase the stock of knowledge". It involves the collection, organization and analysis of evidence to increase understanding of a topic, characterized by a particular att ...

endocrinologist Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...

at the company who was employed to study nonsteroidal estrogen pharmacology, noted the structural similarity of MER-25 to

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

ic TPE derivatives and decided to test the compound for estrogenicity. Instead of the expected estrogenic effects however, Lerner found that MER-25 blocked the effects of estrogens. Lerner subsequently went on to be involved in the discovery of clomifene, the first potently antiestrogenic TPE derivative to be characterized. The structure of clomifene is similar to that of its predecessor, MER-25. Clomifene is about 10-fold more potent as an antiestrogen than MER-25. The

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

of ethamoxytriphetol for the rat ER is approximately 0.06% relative to

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

. For comparison, the affinities of

and

afimoxifene Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development u ...

(4-hydroxytamoxifen) for the rat ER relative to estradiol were 1% and 252%, respectively.

References

{{Estrogen receptor modulators Abandoned drugs Tertiary alcohols Diethylamino compounds Antiestrogens Hormonal antineoplastic drugs Selective estrogen receptor modulators Phenol ethers

See also

References