A Selective Estrogen Receptor Modulator Designed for the Treatment of Uterine Leiomyoma with Unique Tissue Specificity for Uterus and Ovaries in Rats

Hummel, C. W.; Geiser, Andrew G.; Bryant, Henry U.; Ir, Cohen; Dally, Robert; Fong, Kin Chiu; Frank, Scott A.; Hinklin, Ronald J.; Jones, Scott A.; Lewis, George Cornewall; McCann, Denis; Rudmann, Daniel G.; Shepherd, Timothy A.; Tian, Hongqi; Wallace, Owen B.; Wang, Minmin; Wang, Yong; Dodge, Jeffrey A.

doi:10.1021/jm050723z

Cited by 47 publications

(34 citation statements)

References 18 publications

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“…Observations on fluoroestradiols support the hypothesis that toxicity and activity are not intrinsically coupled but are dependent on the chemical structure, which dictates the metabolic profile and characteristics of reactive metabolites. The selection of a 4Ј-amino substituent is interesting mechanistically, because of the likely formation of a quinone imine oxidative metabolite, and a methanesulfonyl group was recently used in a new SERM to limit blood-brain barrier penetration (Hummel et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

Qin¹,

Kastrati²,

Ashgodom³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Raloxifene and arzoxifene are benzothiophene selective estrogen receptor modulators (SERMs) of clinical use in postmenopausal osteoporosis and treatment of breast cancer and potentially in hormone replacement therapy. The benefits of arzoxifene are attributed to improved bioavailability over raloxifene, whereas the arzoxifene metabolite, desmethylarzoxifene (DMA) is a more potent antiestrogen. As polyaromatic phenolics, benzothiophene SERMs undergo oxidative metabolism to electrophilic quinoids. The long-term clinical use of SERMs demands increased understanding of correlations between structure and toxicity, with metabolism being a key component. A homologous series of 4-substituted 4-desmethoxyarzoxifene derivatives was developed, and metabolism was studied in liver and intestinal microsomes. Formation of glutathione conjugates was assayed in rat liver microsomes and novel adducts were characterized by liquid chromatography-tandem mass spectrometry.Formation of glucuronide conjugates was assayed in human intestine and liver microsomes, demonstrating formation of glucuronides ranging from 5 to 100% for the benzothiophene SERMs: this trend was inversely correlated with the loss of parent SERM in rat liver microsomal incubations. Molecular orbital calculations generated thermodynamic parameters for oxidation that correlated with Hammett substituent constants; however, metabolism in liver microsomes correlated with a combination of both Hammett and Hansch lipophilicity parameters. The results demonstrate a rich oxidative chemistry for the benzothiophene SERMs, the amplitude of which can be powerfully modulated, in a predictable manner, by structural tuning of the 4-substituent. The predicted extensive metabolism of DMA was confirmed in vivo and compared with the relatively stable arzoxifene and F-DMA.

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Section: Discussionmentioning

confidence: 99%

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

Qin¹,

Kastrati²,

Ashgodom³

et al. 2008

Drug Metab Dispos

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“…Our previous studies have shown that raloxifene can be bioactivated by rat liver microsomes into quinoids which covalently modified microsomal proteins using the COATag technology (34). It was of interest to determine if raloxifene and DMA could modify uterine microsomal proteins after bioactivation since the uterus is one of the major target tissues of estrogens and antiestrogens in vivo (52). In the current study, by using the biotin conjugated raloxifene and DMA COATags, we observed that both raloxifene and DMA could be oxidized to diquinone methides which further covalently modified rat uterine microsomal proteins (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Uterine Peroxidase-Catalyzed Formation of Diquinone Methides from the Selective Estrogen Receptor Modulators Raloxifene and Desmethylated Arzoxifene

Liu

Qin

Thatcher

et al. 2007

Chem. Res. Toxicol.

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Long term usage of the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer. One potential mechanism of tamoxifen induced carcinogenesis involves metabolism to reactive intermediates, such as an o-quinone, quinone methide, and carbocation. We have previously shown that the benzothiophene SERMs, raloxifene and desmethylated arzoxifene (DMA), can also be bioactivated to electrophilic quinoids by rat/human liver microsomes and rat hepatocytes. Since the uterus is a major target tissue of estrogens and antiestrogens, it was of interest to determine if quinoids could be formed from SERMs in uterine tissue potentially producing cytotoxic effects. Incubations with rat uterine microsomes showed that both raloxifene and DMA could be oxidized to electrophilic di-quinone methides that were trapped as the corresponding GSH conjugates. A new raloxifene GSH-dependent conjugate was identified as raloxifene Cys-Gly that was formed from the hydrolysis of 7-glutathinyl raloxifene by γ-glutamyl transpeptidase. Interestingly, the metabolism of raloxifene and DMA in rat uterine microsomes was not NADPH-dependent and could be inhibited by cyanide and NADPH or enhanced by H 2 O 2 . In addition, co-incubations with the peroxidase substrates guaiacol or o-phenlyenediamine inhibited diquinone methide GSH conjugate formation from both SERMs. Incubations of raloxifene and DMA with horseradish peroxidase (HRP) were studied as models of the interaction between benzothiophene SERMs and peroxidase. The results showed that HRP could directly oxidize raloxifene and DMA to the corresponding dimers via the formation of phenoxyl radicals in the absence of exogenous hydrogen peroxide. In addition, GSH appears to be involved in multiple peroxidase-catalyzed oxidative metabolic pathways of benzothiophene SERMs. Finally, COATag (Covert Oxidatively Activated Tag) methodology, which involves the utilization of biotin conjugated raloxifene and DMA, was used in order to identify target proteins by affinity chromatography.Incubations of raloxifene and DMA COATags with rat uterine microsomes showed several modified proteins by western blot analysis. The protein modification could be enhanced by the addition of H 2 O 2 and decreased by the addition of NADPH suggesting that unlike liver metabolism the formation of quinoids in the uterus could be mediated by uterine peroxidases.

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“…The effect of the number of anchor points is easily explained by the fact that there are more descriptor vectors for the three-anchor search than for the two-anchor search, and the fewest of all for the one-anchor search. Nevertheless, the one-anchor-point 4.0 nm [a] 2.25 11 3 0 cAMP-Dependent protein kinase [36] 1RE8 0.3 nm 2.1 13 5 0 b-Trypsin [36] 1O2Q 21 nm 1.5 5 9 5 HIV-1 protease [37] 2I0D 0.8 pm 1.95 6 7 8 Estrogen receptor [38] 2AYR 0.51 nm 1.9 11 0 0 Tyrosine protein kinase (SRC) [39] 1IS0 100 nm [a] 1.9 6 6 5 Factor Xa [40] 1MQ5 1 nm 2.1 13 0 0 Acetylcholinesterase [41] 1E66 0.13 nm 2.1 3 0 0 Purine nucleoside phosphorylase [42] …”

Section: Prediction Quality Assessmentmentioning

confidence: 99%

SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping

Fontaine¹,

Cross

Plasencia³

et al. 2009

ChemMedChem

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A new method for fragment and scaffold replacement is presented that generates new families of compounds with biological activity, using GRID molecular interaction fields (MIFs) and the crystal structure of the targets. In contrast to virtual screening strategies, this methodology aims only to replace a fragment of the original molecule, maintaining the other structural elements that are known or suspected to have a critical role in ligand binding. First, we report a validation of the method, recovering up to 95% of the original fragments searched among the top-five proposed solutions, using 164 fragment queries from 11 diverse targets. Second, six key customizable parameters are investigated, concluding that filtering the receptor MIF using the co-crystallized ligand atom type has the greatest impact on the ranking of the proposed solutions. Finally, 11 examples using more realistic scenarios have been performed; diverse chemotypes are returned, including some that are similar to compounds that are known to bind to similar targets.

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A Selective Estrogen Receptor Modulator Designed for the Treatment of Uterine Leiomyoma with Unique Tissue Specificity for Uterus and Ovaries in Rats

Cited by 47 publications

References 18 publications

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

Structural Modulation of Oxidative Metabolism in Design of Improved Benzothiophene Selective Estrogen Receptor Modulators

Uterine Peroxidase-Catalyzed Formation of Diquinone Methides from the Selective Estrogen Receptor Modulators Raloxifene and Desmethylated Arzoxifene

SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping

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