EC508 (Estradiol Aminosulfonylbenzoylproline), a Unique and Highly Promising Estradiol Ester and Possible Oral Estradiol Form of the Future

Aly

EC508 (Estradiol Aminosulfonylbenzoylproline), a Unique and Highly Promising Estradiol Ester and Possible Oral Estradiol Form of the Future

By Aly | First published August 2, 2018 | Last modified September 29, 2021

EC508, also known as estradiol 17β-(1-(4-(aminosulfonyl)benzoyl)-L-proline), or somewhat more simply as estradiol aminosulfonylbenzoylproline, is an estradiol ester and prodrug of estradiol which is under development by a small pharmaceutical company called Evestra for potential medical use in menopausal hormone therapy and as a form of hormonal birth control in cisgender women. It is intended for oral administration similarly to certain other orally used estradiol esters and prodrugs like estradiol valerate and estradiol acetate. However, EC508 is very different from conventional estradiol esters, and is far more promising in comparison. This is because from a theoretical standpoint, despite the fact that it is intended for use as an oral form of estradiol, EC508 has a pharmacological profile by this route that is much more similar to that of non-oral estradiol forms like transdermal estradiol and injectable estradiol than to oral administration of estradiol or conventional estradiol esters.

A “first pass” through the intestines and liver normally occurs with oral administration of drugs before they reach the bloodstream. Estradiol is highly susceptible to metabolism in the liver and intestines. For this reason, when estradiol is taken orally, it is overwhelmingly converted into metabolites such as estrone, estrone sulfate, various other estrogen conjugates, and hydroxylated metabolites. These metabolites of estradiol are mostly inactive as estrogens, and with oral administration, the major metabolites like estrone and estrone sulfate circulate in the blood at much higher levels than does estradiol. Although not currently known to be therapeutically consequential, the circulating metabolite profile of oral estradiol is very unphysiological relative to normal hormonal circumstances. The metabolism of estradiol with the oral first pass is so substantial that the oral bioavailability of estradiol, or the amount of an oral dose that reaches the blood as estradiol when compared to the same dose of estradiol infused directly into the blood, is only about 5%. Moreover, there is substantial variability between people in the bioavailability of oral estradiol, with one pharmacokinetic study reporting a range of 0.1 to 12% in different individuals (Wiki). The estradiol levels that are achieved with the same dose of oral estradiol vary considerably in different people, and varying degrees of first-pass metabolism certainly contribute to this. Conventional estradiol esters like estradiol valerate are little different than estradiol with oral administration, due to rapid and probably complete conversion into estradiol during the first pass.

Another consequence of the first pass with oral estradiol is that much higher levels of estradiol are present in the liver than normal or with non-oral estradiol (Wiki). It is estimated that the exposure of the liver to estradiol is around 5 times greater with oral estradiol than with non-oral estradiol. This is of importance because the liver is an estrogen-sensitive organ, with significant expression of estrogen receptors. The liver synthesizes a large number of important proteins and other products that are then released into the bloodstream and regulate biological functions throughout the body. Through activation of estrogen receptors, estrogens can modulate the production of many such liver-derived products (Table). Some of the more well-known examples include sex hormone-binding globulin (SHBG) and blood lipids like cholesterol and triglycerides. Of particular therapeutic concern however is the influence of estradiol and other estrogens on the synthesis of coagulation factors. By modifying the liver synthesis of these proteins, estrogens can have procoagulatory effects and can increase the risk of blood clots and associated cardiovascular problems like stroke and heart attack (Aly, 2020). Physiological levels of estradiol normally only have a small influence on liver synthesis, and effects like strong procoagulation are specific to states of extremely high estradiol levels like pregnancy. However, oral estradiol, due to the liver first pass and particularly at high doses, can result in pregnancy-like changes in liver synthesis and hence on coagulation and associated health risks. This is not something that normally occurs with physiological doses of non-oral estradiol forms, which have a minimal influence even at higher levels (although very high doses of non-oral estradiol can certainly still have such effects).

Because of the first pass and its low bioavailability, substantial variability, unphysiological metabolite pattern, greater impact on liver synthesis, and greater health risks, oral estradiol is a less favorable form of estradiol than are non-oral estradiol forms like transdermal and injectable estradiol. Consequently, it is generally recommended that non-oral estradiol be used instead of oral estradiol where possible. However, oral estradiol is less expensive than certain non-oral forms (e.g., transdermal), is very easy and convenient to use, and has ubiquitous availability (unlike e.g. injectables). As such, it continues to see widespread use, and remains probably the most commonly used form of estradiol in medicine.

EC508 is special because although it is intended as an oral form of estradiol, it is not like oral estradiol or conventional orally used estradiol esters like estradiol valerate. EC508 is different because it appears to bypass the first pass that normally occurs with oral administration. Due to its unique ester, it seems to be resistant to metabolism in the intestines and liver, which limits its conversion into estradiol and estradiol metabolites at this time. This is also notably seen with certain other estrogen esters like estrone sulfate and estramustine phosphate (estradiol normustine phosphate). In addition, and more importantly, because of its unusual ester moiety, EC508 binds with high affinity to a protein called carbonic anhydrase II (CAII) in red blood cells. This binding causes EC508 to be rapidly accumulated and sequestered into blood cells. Estradiol normally goes through the hepatic portal vein, a blood vessel that carries blood from the gastrointestinal tract to the liver, to reach the liver. With EC508, it is taken up into blood cells so quickly that little ultimately seems to reach the liver. Instead, the red blood cells carry EC508 through the portal vein to the bloodstream, which it is then slowly released into. As with other estradiol esters, EC508 has little or no estrogenic activity itself and is only active after being converted into estradiol.

In accordance with the fact that it bypasses the oral first pass, EC508 shows 100% bioavailability in animals. This can be compared in humans to about 5% for oral estradiol and about 43% for ethinylestradiol (EE)—a synthetic relative of estradiol with strongly improved metabolic stability (but also far greater influence on liver synthesis and related health risks than estradiol). As a result of its complete bioavailability, EC508 has 100 times the oral estrogenic potency of estradiol and 10 times that of ethinylestradiol in animals. As such, EC508 would be expected to be active in humans at microgram (μg) doses, similarly to the estimated delivery rates of transdermal estradiol patches (e.g., 25–100 μg/day) as well as to typical doses of ethinylestradiol (e.g., 5–50 μg/day) but in contrast to the 100-fold higher usual doses of oral estradiol (e.g., 0.5–10 mg/day). Further in accordance with it bypassing the oral first pass, EC508 and non-oral estradiol showed little or no effect on liver synthesis at assessed doses in animals, whereas oral estradiol and ethinylestradiol showed marked effects. Lastly, EC508 had a biological half-life of 5 hours in rats, which is relatively long for this species. For this reason, a long duration may be anticipated with EC508 in humans, in contrast to estradiol injected directly into the blood (which has a very short half-life) but similarly to oral, transdermal, and injectable estradiol.

An earlier drug candidate called estradiol sulfamate (E2MATE; J995), which is likewise a special estradiol ester that binds to CAII and bypasses the oral first pass, was discovered by the same research group in the 1990s, and was likewise developed as a new form of oral estradiol. However, it was subsequently found that E2MATE is additionally a highly potent inhibitor of steroid sulfatase (STS) and prevents its own activation by this enzyme into estradiol in humans. This served to abolish its estrogenic effects in the case of humans and resulted in it being not useful for clinical estrogen therapy. E2MATE was also undesirably found to be substantially converted into estrone sulfamate (E1MATE; J994) during the first pass with oral administration. Consequent to these findings, E2MATE was eventually repurposed as an estrogen synthesis inhibitor for treatment of endometriosis, and as of 2017, remains under development for this indication. In contrast to E2MATE, EC508 is not converted into the corresponding estrone variant, and is not thought to be an STS inhibitor, so the problems that E2MATE had are not expected with it.

Taken together, EC508 shows a preclinical and theoretical profile of being an oral form of estradiol that bypasses the first pass with oral administration. As a result, EC508 with oral administration undergoes little or no first-pass metabolism, has high bioavailability, and does not result in excessive estrogenic exposure in the liver. Consequently, EC508 is expected to be orally active at much lower doses than estradiol, to have reduced variability compared to estradiol, to lack an unphysiological metabolite pattern, and to not have disproportionate influence on estrogen-sensitive liver synthesis and associated health risks. In these regards, EC508 shows a favorable and advantageous profile relative to oral estradiol that is analogous to that with non-oral forms of estradiol like transdermal and injectable estradiol but with the convenience of oral administration. For these reasons, EC508 is a pharmaceutical candidate with the potential to supersede not only oral estradiol in clinical practice but also non-oral estradiol and even other clinically used estrogens like ethinylestradiol (e.g., in birth control pills). If it’s successfully developed and approved, EC508 would naturally one day be used in transfeminine hormone therapy as well.

In addition to EC508, the researchers at Evestra synthesized a testosterone equivalent known as EC586 (testosterone 17β-(1-((5-(aminosulfonyl)-2-pyridinyl)carbonyl)-L-proline or slightly more simply as testosterone aminosulfonylpyridinylcarbonylproline). This testosterone ester shows analogous properties to those of EC508, and hence has the potential to be a non-oral-like form of oral testosterone with high bioavailability and potency, a long duration, and lack of disproportionate liver effects—and hence with major advantages over oral testosterone forms available today. In parallel to EC508, EC586 (or similar drugs) could someday be used in transmasculine hormone therapy. The prodrug approach used to create EC508 and EC586 also notably has the potential to be employed with many other drugs.

Update: No Further Development

Patents for EC508 were filed in 2014 and 2017 and publications describing it were published in the scientific literature in 2017. An Investigational New Drug (IND) application for EC508 was tentatively supposed to be filed with the Food and Drug Administration (FDA) in the United States in the second quarter of 2018 (Evestra). However, as of September 2021, there have been no further updates on the development of EC508. In addition, Evestra’s website has since been redesigned and its research pipeline page listing the status of EC508 has been removed. It’s unknown at this time if EC508 and EC586 are still under development or whether further updates on these compounds can be expected.

References

Ahmed, G., Elger, W., Meece, F., Nair, H. B., Schneider, B., Wyrwa, R., & Nickisch, K. (2017). A prodrug design for improved oral absorption and reduced hepatic interaction. Bioorganic & Medicinal Chemistry, 25(20), 5569–5575. [DOI:10.1016/j.bmc.2017.08.027]
Elger, W., Schwarz, S., Hedden, A., Reddersen, G., & Schneider, B. (1995). Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application. The Journal of Steroid Biochemistry and Molecular Biology, 55(3-4), 395–403. [DOI:10.1016/0960-0760(95)00214-6]
Elger, W., Palme, H. J., & Schwarz, S. (1998). Novel oestrogen sulfamates: a new approach to oral hormone therapy. Expert Opinion on Investigational Drugs, 7(4), 575–589. [DOI:10.1517/13543784.7.4.575]
Elger, W., Barth, A., Hedden, A., Reddersen, G., Ritter, P., Schneider, B., Züchner, J., Krahl, E., Müller, K., Oettel, M., & Schwarz, S. (2001). Estrogen Sulfamates: A New Approach to Oral Estrogen Therapy. Reproduction, Fertility, and Development, 13(4), 297–305. [DOI:10.1071/rd01029]
Elger, W., Wyrwa, R., Ahmed, G., Meece, F., Nair, H. B., Santhamma, B., Killeen, Z., Schneider, B., Meister, R., Schubert, H., & Nickisch, K. (2017). Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions. The Journal of Steroid Biochemistry and Molecular Biology, 165, 305–311. [DOI:10.1016/j.jsbmb.2016.07.008]
Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(Suppl 1), 3–63. [DOI:10.1080/13697130500148875] [PDF]
Nickisch, K., Santhamma, B., Ahmed, G., Meece, F., Elger, W., Wyrwa, R., & Nair, H. (2017). U.S. Patent No. 9,745,338. Washington, DC: U.S. Patent and Trademark Office. [US9745338B2]
Nickisch, K., Santhamma, B., Ahmed, G., Meece, F., Elger, W., Wyrwa, R., & Nair, H. (2019). U.S. Patent No. 10,273,263. Washington, DC: U.S. Patent and Trademark Office. [US10273263B2]
Potter, B. V. (2018). SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects. Journal of Molecular Endocrinology, 61(2), T233–T252. [DOI:10.1530/JME-18-0045]
Stanczyk, F. Z., Archer, D. F., & Bhavnani, B. R. (2013). Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception, 87(6), 706–727. [DOI:10.1016/j.contraception.2012.12.011]
Thomas, M. P., & Potter, B. V. (2015). Discovery and development of the aryl O-sulfamate pharmacophore for oncology and women’s health. Journal of Medicinal Chemistry, 58(19), 7634–7658. [DOI:10.1021/acs.jmedchem.5b00386]
Thomas, M. P., & Potter, B. V. (2015). Estrogen O-sulfamates and their analogues: clinical steroid sulfatase inhibitors with broad potential. The Journal of Steroid Biochemistry and Molecular Biology, 153, 160–169. [DOI:10.1016/j.jsbmb.2015.03.012]
von Schoultz, B., Carlström, K., Collste, L., Eriksson, A., Henriksson, P., Pousette, Å., & Stege, R. (1989). Estrogen therapy and liver function—metabolic effects of oral and parenteral administration. The Prostate, 14(4), 389–395. [DOI:10.1002/pros.2990140410]