Discovery and Synthesis of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]- 2-(4-hydroxyphenyl)]benzo[<i>b</i>]thiophene:  A Novel, Highly Potent, Selective Estrogen Receptor Modulator

Palkowitz, Alan D.; Glasebrook, Andrew L.; Thrasher, K. Jeff; Hauser, Kenneth L.; Short, Lorri L.; Phillips, Donald A.; Muehl, Brian S.; Sato, Masahiko; Shetler, Pamela; Cullinan, George J.; Pell, TJ; Bryant, Henry U.

doi:10.1021/jm970167b

Cited by 171 publications

(57 citation statements)

References 27 publications

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“…Reagents BTC {the ''benzothiophene core'' 2-(4-hydroxyphenyl)-benzo[b]thiophen-6-ol} was synthesized following literature procedures and the X-DMA SERMs using our improved methods (20,21). Other reagents were purchased from Sigma unless stated otherwise.…”

Section: Methodsmentioning

confidence: 99%

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Dietz²,

Dunlap

et al. 2007

Molecular Cancer Therapeutics

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The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are ''oxidatively labile'' and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)Hdependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity. [Mol Cancer Ther 2007;6(9):2418 -28]

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Section: Methodsmentioning

confidence: 99%

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Dietz²,

Dunlap

et al. 2007

Molecular Cancer Therapeutics

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“…Further, the raloxifene analogue arzoxifene (Fig. 1C), despite being more potent than tamoxifen or 4-hydroxytamoxifen on inhibition of human mammary carcinoma cell proliferation and on decreasing rat uterine wet weight (Palkowitz et al . 1997, Suh et al .…”

Section: Serms Vs Serds: Two Separate Classes Of Antiestrogens?mentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…Replacement of the carbonyl group by other functionalities has also been investigated [44]. Thus, substitution of the Raloxifene carbonyl with S (69), CH 2 (70) or NH (71) increased the antagonistic activity in the MCF-7 assay 2-5 fold, whereas introduction of oxygen (72) at this position maximized the antagonistic activity 10-fold.…”

Section: Scheme 15mentioning

confidence: 99%

Non-Steroidal Subtype Selective Estrogens

Veeneman¹

2005

CMC

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The biological effects of estrogens are thought to be mediated by two receptors referred to as ERalpha and ERbeta. In recent years significant efforts have been devoted to the design of subtype selective ligands. These ligands are valuable tools to establish the precise biological role of each of the subtypes and to develop new generations of therapeutics. The first part of this review briefly summarizes the biology behind the estrogen receptors. The second part addresses the structure-activity relationship of the subtype selective ER ligands that were reported up to now. In the third part, the current insights in the therapeutic prospects of the subtype selective estrogens will be discussed.

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Discovery and Synthesis of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]- 2-(4-hydroxyphenyl)]benzo[b]thiophene: A Novel, Highly Potent, Selective Estrogen Receptor Modulator

Cited by 171 publications

References 27 publications

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Non-Steroidal Subtype Selective Estrogens

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