Substituted Aminoalkoxytriarylhaloethylenes

Palopoli, Frank P.; Feil, V. J.; Allen, Robert E.; Holtkamp, Dorsey E.; Richardson, A.

doi:10.1021/jm00313a017

Cited by 44 publications

(8 citation statements)

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“…The literature on clomiphene [2-chloro-l-(p-/?-diethylaminoethoxyphenyl) 1,2 diphenylethylene] is confusing because the geometric isomers were originally given the wrong designations with regard to their biological properties. The cis isomer (isomer B) was reported to possess antiestrogenic properties, and the trans isomer (isomer A) was reported to have estrogenic properties in the rat (3)(4)(5). After it was recognized that the nomenclature was incorrect, the isomers were renamed enclomiphene (antiestrogenic trans isomer) and zuclomiphene (estrogenic cis isomer).…”

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confidence: 99%

Geometric Isomers of Substituted Triphenylethylenes and Antiestrogen Action

1981

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The estrogenic and antiestrogenic activities of tamoxifen ICI 47,699, enclomiphene, zuclomiphene, and the geometric isomers of monohydroxytamoxifen and CI628 were determined in the 3-day immature rat uterine weight test. Tamoxifen, enclomiphene, and the releated geometric isomers of monohydroxytamoxifen and CI628 were partially estrogenic with antiestrogenic properties. ICI 47,699 and zuclomiphene were predominantly estrogenic; however, an antiestrogen effect for zuclomiphene (100 micrograms daily) was demonstrable and large doses of ICI 47,699 (1 or 10 mg daily) inhibited full estrogen action. In contrast, the geometric isomers of monohydroxytamoxifen and CI628 related to ICI 47,699 and zuclomiphene were partially estrogenic with antiestrogenic properties. The estrogenic properties of ICI 47,699 were classified in three ways: elevation of uterine wet weight, increase in whole uterine DNA, and increase in the mitotic activity of luminal epithelial cells. In general, ICI 47,699 was able to initiate estrogenic responses of DNA synthesis or mitosis by translocation of fewer cytoplasmic estrogen receptors to the nuclear compartment than tamoxifen. A model is proposed to explain antiestrogen action in terms of the geometric requirements for receptor binding. It is suggested that the position in space of the alkylaminoethoxyside chain is of fundamental importance. Overall, these data lend support to the view that a structurally specific ligand-estrogen receptor complex can influence the future events within a target tissue to produce either an agonist or an antagonist response.

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confidence: 99%

Geometric Isomers of Substituted Triphenylethylenes and Antiestrogen Action

1981

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“…In contrast, chloramiphene (MRL41; clomiphene-to-be; Fig. 2) a potent antifertility agent in animals (6)(7)(8) was a triphenylethylene but an impure mixture of cisand transgeometric isomers (9). The clinically available material today remains a mixture of isomers.…”

Section: The First Nonsteroidal Antiestrogenmentioning

confidence: 99%

Serendipity in the search for “morning-after pills” led to clomiphene for the induction of ovulation

Jordan

2020

F&S Science

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The approval of the oral contraceptive on June 23, 1960, by the United States Food and Drug Administration (FDA), changed society forever. For the first time, a pill designed and tested by men, supported by influential women, allowed women to control their fertility. For the first time, the FDA approved a medicine to be taken by humans without a disease. The chance discovery of a new group of medicines called nonsteroidal antiestrogens, created an opportunity for the pharmaceutical industry. These compounds were shown to be postcoital antifertility agents in rats and mice. In the 1960s, the development of a ''morning-after pill'' would have had an enormous market. Numerous companies focused discovery efforts to evaluate the development of their patented nonsteroidal antiestrogens: Merrell (clomiphene), Upjohn (U-11,100A), and ICI Pharmaceutical Division (ICI46,474). However, the antifertility effects of antiestrogens in rats and mice does not mean that the new medicine would be an antifertility agent in women. In this case, clomiphene did exactly the opposite of what it was predicted to prevent. Clomiphene became the first medicine to induce ovulation in subfertile women. This article describes the twists and turns of drug discovery and development over the past half century. The conclusion emphasizes the evolution of drug development over decades, based on fashions in medical research and discoveries in clinical pharmacology. As a result, new uses for old molecules, that started life as ''nonsteroidal antiestrogens,'' have revolutionized women's health as members of the new group of medicines called selective estrogen receptor modulators. (Fertil Steril Sci Ò 2020;1:3-13. Ó2020 by American Society for Reproductive Medicine.

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“…Discussion. The cis stereochemistry was assigned to (IB) since it exhibited ultraviolet absorption at higher wavelength than (IA) (Palopoli, Feil, Allen, Holtkamp & Richardson, 1967).…”

Section: Atomic Positional and Thermal Parametersmentioning

confidence: 99%