Androstenediol analogs as ER-β-selective SERMs

Blizzard, Timothy A.; Gude, Candido; Morgan, Jerry D.; Chan, Wanda; Birzin, Elizabeth T.; Mojena, Marina; Tudela, Consuelo; Chen, Fang; Knecht, Kristin; Su, Qin; Kraker, Bryan; Mosley, Ralph T.; Holmes, Mark A.; Sharma, Nandini; Fitzgerald, Paul J.; Rohrer, Susan P.; Hammond, Milton L.

doi:10.1016/j.bmcl.2005.11.014

Cited by 25 publications

(12 citation statements)

References 27 publications

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“…The literature was extensively surveyed to collect as many structurally diverse ERb ligands as possible (1-119, see Table A and Figure A in Supporting Information) [2,3,6,8,9,11,16,17,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. The collected compounds were carefully selected from around 800 reported inhibitors in such a way to guarantee dissimilar affinities to ERa and ERb, and therefore, to allow access to selective ERb pharmacophore models.…”

Section: Data Mining and Conformational Coveragementioning

confidence: 99%

“…Despite extensive modeling efforts to understand ERa/ligand affinity and selectivity [87][88][89][90][91][92], the area of ERb medicinal chemistry is generally devoid of significant modeling efforts except for some studies [1,2,8,16,17,91,92]. The presence of reasonable crystal structures for ERb directed most modeling studies towards docking experiments [18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 98%

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Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

Taha

Tarairah

Zalloum

et al. 2010

Journal of Molecular Graphics and Modelling

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Section: Data Mining and Conformational Coveragementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

Taha

Tarairah

Zalloum

et al. 2010

Journal of Molecular Graphics and Modelling

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“…tamoxifen) allows them to bind with comparable affinity to the ERs. However, the recent discovery of ERβ subtype and the consequent hypothesis that ER subtypes have discrete function, prompted researchers to explore the possibility of receptor subtype-selective compounds called Selective Estrogen Receptor Subtype Modulators, SERSM [28,[239][240][241]. This Toremifene is extensively metabolized by cytochrome CYP3A4 enzyme in human liver microsomes and cytochrome P450 [216].…”

Section: Selective Estrogen Receptor Alpha Modulators (Serams)mentioning

confidence: 98%

Medicinal Chemistry and Emerging Strategies Applied to the Development of Selective Estrogen Receptor Modulators (SERMs)

Musa¹,

Khan²,

Cooperwood³

2007

CMC

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Selective estrogen receptor modulators (SERMs), known previously as "antiestrogens", are a new category of therapeutic agents used for the prevention and treatment of diseases such as osteoporosis and breast cancer. SERMs act as ER-agonist in some tissues while acting as ER-antagonist in others based on conformational change of the receptors, particularly at the helix 12. Currently, there are two classes of clinically approved SERMs; triphenylethylene derivatives (e.g., tamoxifen) and benzothiophene derivatives (e.g., raloxifene). Tamoxifen, raloxifene and toremifene are the most widely used SERMs. Tamoxifen, an antagonist of the breast tissue, is the first clinically identified compound with noticeable SERM activity. Although tamoxifen has been very successful in breast cancer treatment, its agonistic effect on the uterus is said to be associated with increase risk of developing endometrial cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagonist in the breast and uterus. Therefore, the therapeutic goal of SERMs is the prevention of estrogen deficiency diseases without promoting estrogen-associated tumor growth. Therefore, the objective of this review is to summarize various effects that have been applied in improving the tissue-selectivity of SERMs, highlighting the emerging understanding of their mechanism of actions in selected target tissues and the development of the SERMs. The significance in recent discovery of selective estrogen receptor alpha modulators, SERAMs will also be reviewed.

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“…Very recently, Merck released a series of 19-substituted androstenediols (compound 38), that are ERβ-selective ligands. [50,142,143]. The most ERβ-selective compound (38a; 212-fold) contains a vinyl group that is proposed to interact with the same amino acids as compound 37.…”

Section: Er Subtype-selective Ligandsmentioning

confidence: 99%

Estrogen receptor modulator review

Ullrich¹,

Miller

2006

Expert Opinion on Therapeutic Patents

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The past few years have seen considerable advances in the development of estrogen receptor (ER) modulators and in the understanding of their interaction on estrogen pathways. Whilst prototypical steroidal estrogen agonists have long been appreciated for their use in female contraception and estrogen replacement therapy, more recent investigations have focused on subtype estrogen receptor modulators with selectivity for use in rapidly expanding treatment modalities. As estrogenic effects are primarily mediated through two receptors, defined as ERα and ERβ, significant interest has been dedicated to identifying subtype-selective agonists, antagonists and selective estrogen receptor modulators (SERMs). Additional effort has been dedicated to finding non-subtype-selective SERMs with new utility or improved profiles. Many of these recently identified ligands represent real advances in terms of their preclinical profile with the potential to one day provide novel treatments. This review highlights recent developments on the structural and biological data reported for ER modulators in the patent and scientific literature during the period 2003 -2005.

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Androstenediol analogs as ER-β-selective SERMs

Cited by 25 publications

References 27 publications

Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

Medicinal Chemistry and Emerging Strategies Applied to the Development of Selective Estrogen Receptor Modulators (SERMs)

Estrogen receptor modulator review

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