Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions

Elger, W.; Wyrwa, Ralf; Ahmed, Gulzar; Meece, Frederick A.; Nair, Hareesh B.; Santhamma, Bindu; Killeen, Zachary; Schneider, Birgitt; Meister, Reinhard; Schubert, Harald; Nickisch, Klaus

doi:10.1016/j.jsbmb.2016.07.008

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…The drug was very safe and well tolerated, and the role of STS in activating the sulphamate derivative as a pro-drug was firmly established (Chander et al 2004). However, oestrogenic activity was subsequently significantly limited in humans by metabolic deactivation at C-17, most likely in the gut, and this issue needs to be overcome for further development of the idea (Elger et al 2017).…”

Section: Hormone Replacement Therapymentioning

confidence: 99%

SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects

Potter¹

2018

Journal of Molecular Endocrinology

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Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl -sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.

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Section: Hormone Replacement Therapymentioning

confidence: 99%

SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects

Potter¹

2018

Journal of Molecular Endocrinology

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“…Notably, levels in angiotensinogen (AGT), the most discriminatory protein, separated users and non-users of hormonal contraceptives, and might serve as a biomarker of contraceptive use. Indeed, exogenous estrogens have been reported to cause upregulation of hepatic angiotensinogen (Elger et al, 2017; Gordon et al, 1992) associated with an activation of the renin angiotensin system with however little renal and systemic consequences (Cherney et al, 2007; Kang et al, 2001). A sensitivity analysis unequivocally underscored the necessity of incorporating hormonal contraceptive use into the analytical models, in order to prevent proteins influenced by this treatment from being erroneously linked to factors such as age, sex, or correlated phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study

Dordevic,

Dierks,

Hantikainen

et al. 2023

Preprint

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Large-scale plasma proteomics in population studies offer new avenues to explore non-genetic associations, such as biomarkers for lifestyle and environmental exposure. Moreover, through longitudinal monitoring, they help in characterizing the onset and progression of diseases. Utilizing the SWATH DIA-MS-based proteomic approach with 5-minute chromatographic gradients, we examined the neat plasma proteome of 3,632 participants from the Cooperative Health Research in South Tyrol (CHRIS) study. We present precise protein quantities for 148 highly abundant plasma protein groups. Many of these proteins are challenging to quantify using affinity-based reagents. This set of highly abundant plasma proteins includes immunoglobulins, coagulation factors, metabolic proteins, and components of the innate immune system, such as the complement system. Our findings indicate that, beyond age and sex, the most significant biological variable affecting the plasma proteome was the use of hormonal contraceptives. The signature from this drug class was more pronounced compared to other common medications, which influenced only a subset of the measured proteins and exhibited smaller effect sizes. Notably, Angiotensinogen (AGT) levels were strongly influenced by contraceptive use, suggesting that AGT levels might serve as a potential biomarker for contraceptive usage. Due to its high prevalence, and apparently strong influence, this type of medication should be accounted for in any epidemiological or clinical study of the plasma proteome to avoid spurious findings.

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“…Frontiers in Pharmacology frontiersin.org 2017). Androstenedione is then converted to estrone and testosterone is converted to estradiol (Fukami and Ogata, 2022).…”

Section: Biosynthesis and Metabolism Of Estrogenmentioning

confidence: 99%

“…However, some observational studies revealed that the risk of VTE in patients administered estrogen via subcutaneous injection was much lower than that in the orally administered estrogen group ( Scarabin et al, 2003 ; Laliberté et al, 2018 ). The higher risk of VTE associated with oral estrogen is attributed to its effects on the liver, leading to an increase in some hepatogenic coagulation factors ( Elger et al, 2017 ). The reason for the lower risk of VTE when estrogen is administered via the subcutaneous route is that estrogen can alter the number and function of platelets.…”

Section: Estrogen and Covid-19mentioning

confidence: 99%

Biofunctional roles of estrogen in coronavirus disease 2019: Beyond a steroid hormone

Wang

Mao²,

Tai³

et al. 2022

Front. Pharmacol.

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The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), epidemic poses a major global public health threat with more than one million daily new infections and hundreds of deaths. To combat this global pandemic, efficient prevention and management strategies are urgently needed. Together with the main characteristics of COVID-19, impaired coagulation with dysfunctions of the immune response in COVID-19 pathophysiology causes high mortality and morbidity. From recent clinical observations, increased expression of specific types of estrogen appears to protect patients from SARS-CoV-2 infection, thereby, reducing mortality. COVID-19 severity is less common in women than in men, particularly in menopausal women. Furthermore, estrogen levels are negatively correlated with COVID-19 severity and mortality. These findings suggest that estrogen plays a protective role in the pathophysiology of COVID-19. In this review, we discuss the potential roles of estrogen in blocking the SARS-CoV-2 from invading alveolar cells and replicating, and summarize the potential mechanisms of anti-inflammation, immune modulation, reactive oxygen species resistance, anti-thrombosis, vascular dilation, and vascular endothelium protection. Finally, the potential therapeutic effects of estrogen against COVID-19 are reviewed. This review provides insights into the role of estrogen and its use as a potential strategy to reduce the mortality associated with COVID-19, and possibly other viral infections and discusses the possible challenges and pertinent questions.

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Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions

Cited by 5 publications

References 22 publications

SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects

SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects

Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study

Biofunctional roles of estrogen in coronavirus disease 2019: Beyond a steroid hormone

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