Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal in

doi:10.1021/JM00374A021

Paper

Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal in

Published Aug 1, 1984 · C. D. Jones, M. G. Jevnikar, A. Pike

Journal of medicinal chemistry

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260

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1

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Abstract

In an effort to prepare nonsteroidal antiestrogens demonstrating greater antagonism and less intrinsic estrogenicity than those currently available, a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives was synthesized. These compounds were prepared by Friedel-Crafts aroylation of appropriate O-protected 2-arylbenzo[b]thiophene nuclei with basic side-chain-bearing benzoyl chlorides followed by removal of the protective groups to provide the desired compounds containing both hydroxyl and basic side-chain functionality. A particularly useful method for the cleavage of aryl methoxy ethers without removal of (dialkylamino)ethoxy side chain functionality elsewhere in the molecule was found to be AlCl3/EtSH. The benzothiophene derivatives were tested for their ability to inhibit the growth-stimulating action of estradiol on the immature rat uterus. Seemingly minor changes in the side-chain amine moiety were found to have profound effects on the ability of the compounds to antagonize estradiol. Analogues having basic side chains containing cyclic (pyrrolidine, piperidine, and hexamethyleneamine) moieties were found to have less intrinsic estrogenicity and to antagonize estradiol action more completely than their noncyclic counterparts. The most effective antiestrogen in the series, compound 44, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, elicited a modest uterotropic activity that did not increase with increasing dose. In antagonism of estradiol, 44 exhibited a degree of inhibition surpassing that of tamoxifen at any dose tested. The new benzothiophene antiestrogen was also shown to have high affinity for rat uterine cycloplasmic estrogen receptor and to be an inhibitor of the growth of DMBA-induced rat mammary tumors.

In Vitro Study

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Study Snapshot

The synthesized 3-aroyl-2-arylbenzo[b]thiophene derivatives show potential as effective nonsteroidal antiestrogens with less intrinsic estrogenicity and greater antagonism than current options.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]-phenyl]methanone hydrochloride (LY156758), a remarkably effective estrogen antagonist with only minimal in

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References

Citations

Molecular structure, electronic properties, spectroscopic investigation and nonlinear optical properties of thianaphthene-2-carboxylic acid: A quantum chemical approach

This study presents a detailed theoretical analysis of Thianaphthene-2-carboxylic acid, a thiophene derivative, revealing its optimized geometric structure, electronic properties, and nonlinear optical characteristics.

Modular and Regioselective Synthesis of Benzo-Fused Five-Membered Rings Enabled by Co/Ti Synergism.

This study presents a general and regioselective method for constructing benzo-fused five-membered rings using 1,2-Co/Ti heterobimetallic arylene and benzotitanole intermediates under CoBr2/bipyridine catalysis.

Synthesis Studies and the Evaluation of C6 Raloxifene Derivatives.

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Synthesis, Crystal Structure, Hirshfeld, DFT, Molecular Docking, Dynamics Studies, and Anti-cancer Activity of 1-Substituted-2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates

Compound 6j shows promising anti-cancer activity against lung adenocarcinoma A549 and breast cancer MCF-7 cells, with no cytotoxicity observed and early apoptosis induction.

Fused thiophene as a privileged scaffold: A review on anti-Alzheimer's disease potentials via targeting cholinesterases, monoamine oxidases, glycogen synthase kinase-3, and Aβ aggregation.

Fused thiophene derivatives show potential in treating Alzheimer's disease by targeting cholinesterases, monoamine oxidases, glycogen synthase kinase-3, and A aggregation.

A review on the synthesis and biological relevance of benzo[b]thiophene derivatives

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Aryl Dance Reaction of Arylbenzoheteroles.

AlCl3 efficiently converts C3-arylheteroles to C2-arylheteroles, and Zn(OTf)2 can also catalyze C2- to C3-arylheterole conversion depending on substrate electron density.

Silica gel-assisted synthesis of benzo[b]thiophenes from o-(alkylsulfanyl)(ethynyl)benzenes

Silica gel-assisted synthesis of benzo[b]thiophenes from o-(alkylsulfanyl)(ethynyl)benzenes yields various 2-substituted benzo[b]thiophenes, with tert