Nonsteroidal Antiestrogens

Tamoxifen was not the first antiestrogen but the value of the drug slowly increased as the fashions in research changed. During the late 1950s and throughout the 1960s there was a focus on the development of new contraceptives in the wake of the success of oral contraceptives. These medicines did not treat a disease but altered lifestyle so there was huge potential for widespread use. But the application of antiestrogens as contraceptives failed and the compounds were drugs looking for a disease to treat! This perspective changed following the start of the 'War on Cancer' declared on 23 December 1971. There were now incentives to conduct translational cancer research and introduce new treatments. Regrettably, the process was slow for the introduction of targeted treatments as all hopes were initially pinned on combination cytotoxic chemotherapy to cure cancer.

In 1958, Lerner and coworkers at the William S. Merrell Company reported the biological properties of the first nonsteroidal antiestrogen, MER25 (Figure 1).6 The discovery of nonsteroidal antiestrogens was an example of serendipity and is best described in Lerner's own words7:

As 1954 was drawing to its end a triphenylethanol compound was synthesized, not for the purpose of investigation for estrogen antagonism but for testing by the cardiovascular research section at Merrell since it had been


MER25 (ethamoxytriphetol)

Enclomiphene MRL41 (trans isomer)

MER29 (triparanol)

Zuclomiphene MRL41 (cis isomer)

Figure 1 The formulae of the first nonsteroidal antiestrogen, MER25, and the structurally related compound MER29 used to lower circulating cholesterol. MER29 was withdrawn from the market because of the increased incidence of cataracts. The next antiestrogen, MRL41, was a mixture of the cis and trans isomers of a substituted triphenylethylene later named clomiphene.

reported that a related compound had some effect on blood flow. A request for a sample of that compound for study as a possible estrogen antagonist was answered by the cardiovascular system pharmacologist with his entire supply since it was essentially inactive in his studies. This compound, 1-(p-1 diethylamino-ethoxyphenyl)-2(/>-methoxyphenyl)-1-phenylethanol was tested in immature mice at the arbitrary 3-day screening dose of 5 mg. It was administered subcutaneously twice daily for three days alone or in combination with 0.03 mg of estradiol benzoate, and the uterine weight and intraluminal fluid served as the end points to be measured on the day after the last treatment. The results of this study were highly questioned since neither the uteri of the mice administered the compound alone nor the uteri of the animals receiving the compound plus estrogen were significantly heavier than those of controls treated with olive oil vehicle alone. It was thought that this was a 'bad study.' The compound, however, was retested and the results were identical to those of the first study. The increase in uterine weight and intraluminal fluid by estradiol treatment was completely prevented by simultaneous administration of the compound that was eventually to be called MER25 or ethamoxytriphetol.

The compound was found to be an antiestrogen in all species tested and was found to have no other hormonal or antihormonal properties. However, the discovery MER25 was considered to be of importance at the time because the compound was a postcoital contraceptive in laboratory animals.8-10 Obviously, one application could have been as a 'morning-after pill' but after clinical evaluation in numerous situations the results were disappointing. MER25 underwent initial evaluation for the induction of ovulation11 and the treatment of chronic cystic mastitis, breast and endometrial carcinoma12'13 but the low potency and severe side effects on the central nervous system prohibited further clinical development.7

It is relevant to point out that the antiestrogen MER25 is a structural derivative of the cholesterol-lowering drug triparanol (MER29) (Figure 1). In the late 1950s there was initial enthusiasm about the potential benefits of triparanol as a hypocholesterolemic drug.14 However, the finding that triparanol caused an accumulation of desmosterol (an intermediate in cholesterol biosynthesis)15-18 and the linking of this biochemical effect to cataract formation,19-21 caused withdrawal of the drug in 1962 (Figure 2). Nevertheless, triparanol was first evaluated as a potential therapy for breast cancer22 but again the results were disappointing.

A successor compound to MER25, MRL41 or clomiphene (Figure 1), was a more potent antiestrogen but drug development for long-term use was to be retarded because of toxicological concerns. Clomiphene is an effective antifertility agent in laboratory animals23 but paradoxically induces ovulation in subfertile women.24-26 Again, the prospect of developing a 'morning-after pill' for women was not realized. Although clomiphene showed some activity in



->- Dihydrolanosterol












Figure 2 The mechanism of action of triparanol is to inhibit cholesterol biosynthesis but also to increase demosterol levels which is implicated in cataract formation. In contrast, tamoxifen has an alternate mechanism of action to lower cholesterol levels.



U-11,100A (nafoxidine)


Figure 3 The formulae of compounds discovered by the Upjohn Company as antifertility agents. Nafoxidine subsequently was tested as a therapy for breast cancer but development was not pursued because of toxic side effects experienced by the majority of patients. Two observations merit comment. The fixed ring structure confirmed the idea that a 'trans-like' structure was necessary for potent antifertility and, later, antiestrogenic activity. The compound U-11,555A became a template for numerous agents developed throughout the 1990s and into the twenty first Century.

the treatment of advanced breast cancer,27'28 the drug was only developed for short-term use for the induction of ovulation29 because desmosterol was noted in patient sera during prolonged treatment.30

Clomiphene is marketed as an impure mixture of geometric isomers (Figure 1) which have opposing biological activities: one isomer is an estrogen and one isomer is an antiestrogen.31 Unfortunately the isomers were initially (1967) given the incorrect designation but this was corrected by 1976.32 Although breast cancer clinical trials were still being reported with the impure mixture of isomers in 1974, the antiestrogenic isomer eventually entered into clinical trial for breast cancer treatment but the studies were dropped by the National Institutes of Health (NIH) due to the interest in tamoxifen (Figure 2).33

In contrast, the compound nafoxidine (U-11,100A)34'35 and U-11,555A36 are dihydronaphthalene and indene derivatives respectively and therefore cannot isomerize (Figure 3). The drugs are potent antiestrogens with antifertility properties in laboratory animals.37-39 Subsequent studies by Terenius40 demonstrated tight and somewhat irreversible binding of nafoxidine to the estrogen receptor derived from mouse target tissues. Nafoxidine exhibits antitumor properties in laboratory models of kidney cancer in the hamster41 and the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model42 but following extensive testing as a treatment for breast and renal cancer, the drug was not developed further because of unacceptable side effects experienced by all patients.43,44

Figure 4 The formula of the mixed estrogen/antiestrogen ICI46,474 and its estrogenic isomer ICI47,699 discovered in antifertility screens at ICI Pharmaceuticals Division. The trans isomer designated ICI46,474 was eventually developed as the breast cancer drug tamoxifen (Nolvadex).

ICI46,474 (tamoxifen)

ICI47,699 (cis isomer)

Figure 4 The formula of the mixed estrogen/antiestrogen ICI46,474 and its estrogenic isomer ICI47,699 discovered in antifertility screens at ICI Pharmaceuticals Division. The trans isomer designated ICI46,474 was eventually developed as the breast cancer drug tamoxifen (Nolvadex).

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