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Other names | EC-508; Estradiol 17β-(1-(4-(aminosulfonyl)benzoyl)-L-proline); Estra-1,3,5(10)-triene-3,17β-diol 17β-(1-[4-(aminosulfonyl)benzoyl]-L-proline); 3-Hydroxyestra-1,3,5(10)-trien-17β-yl 1-[4-(aminosulfonyl)benzoyl]-L-proline |
Drug class | Estrogen; Estrogen ester |
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Chemical and physical data | |
Formula | C30H36N2O6S |
Molar mass | 552.69 g·mol−1 |
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EC508, also known as estradiol 17β-(1-(4-(aminosulfonyl)benzoyl)-L-proline), is an estrogen which is under development by Evestra for use in menopausal hormone therapy and as a hormonal contraceptive for the prevention of pregnancy in women. [1] [2] [3] [4] It is an orally active estrogen ester – specifically, a C17β sulfonamide–proline ester of the natural and bioidentical estrogen estradiol – and acts as a prodrug of estradiol in the body. [2] [3] However, unlike oral estradiol and conventional oral estradiol esters such as estradiol valerate, EC508 undergoes little or no first-pass metabolism, has high oral bioavailability, and does not have disproportionate estrogenic effects in the liver. [2] [3] As such, it has a variety of desirable advantages over oral estradiol, similarly to parenteral estradiol, but with the convenience of oral administration. [2] [3] EC508 is a candidate with the potential to replace not only oral estradiol in clinical practice, but also ethinylestradiol in oral contraceptives. [2] [3] Evestra intends to seek Investigational New Drug status for EC508 in the second quarter of 2018. [1]
Relative to parenteral routes of estradiol like vaginal, transdermal, and injection, oral estradiol is characterized by low bioavailability and disproportionate effects on liver protein synthesis. [2] [3] Due to extensive metabolism during the first-pass into estrone and estrogen conjugates like estrone sulfate, the oral bioavailability of estradiol and conventional estradiol esters like estradiol valerate is only about 5%, and there is high interindividual variability in estradiol levels achieved. [5] Moreover, because of the first-pass, estradiol levels in the liver are 4 or 5 times higher with oral estradiol than those in the circulation. [6] As a result, oral estradiol has disproportionate estrogenic effects on the hepatic production of lipids, hemostatic factors, growth hormone/insulin-like growth factor 1 axis proteins, angiotensinogen, and other proteins. [2] [3] [5] This is unfavorable and may result in an increased risk of venous thromboembolism, cardiovascular events, and other adverse effects. [2] [3] [5]
The pharmacokinetics of EC508 were assessed in rats; its bioavailability was found to be complete (100%), its clearance in blood was low, and its biological half-life was prolonged at about 5 hours. [2] [3] A single oral dose of 5.0 mg/kg EC508 in rats resulted in peak levels of estradiol of 6,104 ng/mL (6,104,000 pg/mL). [2] EC508 itself showed poor activity as an agonist of the estrogen receptor, with an EC50 value of 432 nM relative to 2.3 nM for estradiol (a 188-fold difference), indicating that the estrogenic activity of the compound is solely due to hydrolysis into estradiol. [3] EC508 showed very high oral estrogenic potency, around 100 times that of estradiol and 10 times that of ethinylestradiol in rats. [2] [3] This was determined by uterotrophic effect in ovariectomized rats; an oral dosage of 10 μg/day resulted in uterine weight doubling with EC508, while no effect was observed with estradiol and only a small effect on uterine weight was measured with ethinylestradiol. [2] [3] Conversely, across the dosages assessed, oral estradiol and ethinylestradiol showed marked effects on HDL cholesterol and angiotensinogen levels, while oral EC508 and parenteral estradiol showed no effect at all on these hepatic proteins. [2] [3] These findings are in accordance with the notion that oral EC508, unlike oral estradiol and ethinylestradiol but similarly to parenteral estradiol, bypasses first-pass metabolism and the liver. [2] [3]
The absence of first-pass metabolism and lack of disproportionate liver exposure with EC508 is thought to be due to reversible binding of the sulfonamide moiety of EC508 to an enzyme called carbonic anhydrase II (CAII). [2] [3] EC508 shows moderate affinity for human CAII, with an IC50 for binding inhibition of 110 nM. [2] [3] CAII is highly concentrated in erythrocytes (red blood cells), which are present in large quantity in the blood of the hepatic portal vein. [2] [3] It is believed that following its absorption in the intestines and its entrance into the hepatic portal vein, EC508 is taken up by and massively accumulated in erythrocytes, which prevents it from entering the liver and results in it being transported by erythrocytes straight into the circulation. [2] [3] From circulating erythrocytes, EC508 is thought to be slowly released and then hydrolyzed into estradiol. [2] [3] However, one sulfonamide ester of estradiol related to EC508 known as EC518 showed similar properties with very low or absent binding to CAII and hence probably lacking erythrocyte binding, which raises questions about the necessity of CAII binding for such properties and the mechanism by which they occur. [2]
Estradiol sulfamate (E2MATE) is a C3 sulfamate ester of estradiol which was developed in the 1990s and was a predecessor of EC508. [2] [3] [7] [8] [9] It binds to CAII, is taken up into and stored within erythrocytes, and shows similar properties to EC508. [2] [3] As a result, E2MATE was under development for potential clinical use as an oral estrogen. [2] [3] However, it showed no increase in estradiol levels and no estrogenic effects in human clinical trials. [2] [3] It appears that there are species differences with E2MATE between rats and primates and that the lack of activity in humans is because E2MATE additionally acts as a highly potent inhibitor of steroid sulfatase. [2] [3] [10] This enzyme is responsible for the hydrolysis of sulfur-based estradiol esters like E2MATE and EC508 into estradiol. [2] [3] By inhibiting steroid sulfatase, E2MATE prevents its own activation into estradiol, which effectively abolishes its estrogenic activity. [2] [3] In addition, it was found that E2MATE was substantially transformed into estrone sulfamate (EMATE) in erythrocytes, which may have further impeded its capacity to be activated into estradiol. [2] In contrast to E2MATE, EC508 is not thought to be a steroid sulfatase inhibitor and cannot be transformed into the corresponding estrone equivalent. [2] [3]
A C17β sulfonamide–proline testosterone ester known as EC586, which has similar properties to those of EC508, is also under development by Evestra, specifically as an androgen and potent oral testosterone prodrug for use in androgen replacement therapy in men. [1] [3] Clinical trials for EC586 and EC508 are undergoing as of 2023. [11]
Equilin is a naturally occurring estrogen sex hormone found in horses as well as a medication. It is one of the estrogens present in the estrogen combination drug preparations known as conjugated estrogens and esterified estrogens. CEEs is the most commonly used form of estrogen medications in hormone replacement therapy (HRT) for menopausal symptoms in the United States. Estrone sulfate is the major estrogen in CEEs while equilin sulfate is the second major estrogen in the formulation, present as about 25% of the total.
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.
Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual estrogen and chemotherapy medication which is used in the treatment of prostate cancer in men. It is taken multiple times a day by mouth or by injection into a vein.
Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.
An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.
Ethinylestradiol sulfonate (EES), sold under the brand names Deposiston and Turisteron among others, is an estrogen medication which has been used in birth control pills for women and in the treatment of prostate cancer in men. It has also been investigated in the treatment of breast cancer in women. The medication was combined with norethisterone acetate in birth control pills. EES is taken by mouth once per week.
A steroid ester is an ester of a steroid. They include androgen esters, estrogen esters, progestogen esters, and corticosteroid esters. Steroid esters may be naturally occurring/endogenous like DHEA sulfate or synthetic like estradiol valerate. Esterification is useful because it is often able to render the parent steroid into a prodrug of itself with altered chemical properties such as improved metabolic stability, water solubility, and/or lipophilicity. This, in turn, can enhance pharmacokinetics, for instance by improving the steroid's bioavailability and/or conferring depot activity and hence an extended duration with intramuscular or subcutaneous injection.
Irosustat is an orally active, irreversible, nonsteroidal inhibitor of steroid sulfatase (STS) and member of the aryl sulfamate ester class of drugs that was under development by Sterix Ltd and Ipsen for the treatment of hormone-sensitive cancers such as breast cancer, prostate cancer, and endometrial cancer but has not yet been marketed. The drug was first designed and synthesized in the group of Professor Barry V L Potter at the Department of Pharmacy & Pharmacology, University of Bath, working together with Professor Michael J. Reed at Imperial College, London and its initial development was undertaken through the university spin-out company Sterix Ltd and overseen by Cancer Research UK (CRUK). Results of the "first-in-class" clinical trial in breast cancer of an STS inhibitor in humans were published in 2006 and dose optimisation studies and further clinical data have been reported.
Estradiol sulfamate, or estradiol-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which is under development for the treatment of endometriosis. It is the C3 sulfamate ester of estradiol, and was originally thought to be a prodrug of estradiol.
Estrone sulfamate, or estrone-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which has not yet been marketed. It is the C3 sulfamate ester of the estrogen estrone. Unlike other estrogen esters however, EMATE is not an effective prodrug of estrogens. A closely related compound is estradiol sulfamate (E2MATE), which is extensively metabolized into EMATE and has similar properties to it.
An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.
Estrone sulfate (E1S) is an estrogen medication and naturally occurring steroid hormone. It is used in menopausal hormone therapy among other indications. As the sodium salt, it is the major estrogen component of conjugated estrogens (Premarin) and esterified estrogens. In addition, E1S is used on its own as the piperazine salt estropipate. The compound also occurs as a major and important metabolite of estradiol and estrone. E1S is most commonly taken by mouth, but in the form of Premarin can also be taken by parenteral routes such as transdermal, vaginal, and injection.
EC586, also known as testosterone 17β-(1- -L-proline), is an androgen and anabolic steroid which is under development by Evestra for use in androgen replacement therapy in men. It is an orally active androgen ester – specifically, a C17β sulfonamide–proline ester of the natural and bioidentical androgen testosterone – and acts as a prodrug of testosterone in the body. However, unlike oral testosterone and conventional oral testosterone esters such as testosterone undecanoate, EC586 has high oral potency, may undergo little or no first-pass metabolism, and may not have disproportionate androgenic effects in the liver. As such, it may have a variety of desirable advantages over oral testosterone, similarly to parenteral testosterone, but with the convenience of oral administration. Evestra intends to seek Investigational New Drug status for EC586 in the fourth quarter of 2018.
Estriol sulfamate, or estriol 3-O-sulfamate, is a synthetic estrogen and estrogen ester which was never marketed. It is the C3 sulfamate ester of estriol. The drug shows substantially improved oral estrogenic potency relative to estriol in rats but without an increase in hepatic estrogenic potency. However, the closely related compound estradiol sulfamate (E2MATE) failed to show estrogenic activity in humans, which is due to the fact that it is additionally a highly potent inhibitor of steroid sulfatase which regulates the estrogenicity of such compounds and thus it prevents its own bioactivation into estradiol.
Ethinylestradiol sulfamate, or 17α-ethynylestradiol 3-O-sulfamate, is a synthetic estrogen and estrogen ester which was never marketed. It is the C3 sulfamate ester of ethinylestradiol. The drug shows considerably improved oral estrogenic potency (uterotrophic) relative to ethinylestradiol in rats but without an increase in hepatic estrogenic potency. Related compounds like ethinylestradiol N,N-diethylsulfamate (J271) and ethinylestradiol pyrrolidinosulfonate (J272) have also been developed, and have similar properties in animals. However, the closely related compound estradiol sulfamate (E2MATE) failed to show estrogenic activity in humans, which is due to the fact that it is additionally a highly potent inhibitor of steroid sulfatase and prevents its own bioactivation into estradiol.
Ethinylestradiol sulfate, also known as 17α-ethynylestradiol 3-sulfate, is an estrogen ester – specifically, the C3 sulfuric acid (sulfate) ester of the synthetic estrogen ethinylestradiol (EE) – and is the major metabolite of EE. Circulating levels of EE sulfate range from 6 to 22 times those of EE when EE is taken orally. EE sulfate can be transformed back into EE (14–21%) via steroid sulfatase, and it has been suggested that EE sulfate may serve as a circulating reservoir for EE, similarly to the case of estrone sulfate with estradiol. However, the EE sulfate pool with EE is far smaller than the pool of estrone sulfate that occurs with estradiol. In addition, in contrast to the case of estrone sulfate and estrone, the conversion rate of EE sulfate back into EE is relatively low, and has been said probably isn't of clinical significance. However, other studies have suggested that EE sulfate may nonetheless contribute up to 20% of total EE levels.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.