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EC508: A Groundbreaking Parenteral-Like Oral Form of Estradiol and the Possible Estradiol of the Future

By Aly W. | First published August 2, 2018 | Last modified October 5, 2020

See the following passage from the EC508 Wikipedia article as well as the rest of the article:

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. 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. 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. As such, it has a variety of desirable advantages over oral estradiol, similarly to parenteral estradiol, but with the convenience of oral administration. EC508 is a candidate with the potential to replace not only estradiol in clinical practice, but also ethinylestradiol in oral contraceptives. Evestra intends to seek Investigational New Drug status for EC508 in the second quarter of 2018.

A summary of key points about EC508:

  • EC508 is a C17β sulfonamide–proline ester of estradiol (E2) and a prodrug of E2 in the body
  • It binds to carbonic anhydrase II (CAII) in erythrocytes (red blood cells), which results in it bypassing the liver when administered orally
  • It is stored in and slowly released from erythrocytes into the blood, which results in it having a long duration
  • The oral bioavailability of EC508 is 100% (relative to ~5% for E2 and 43% for ethinylestradiol (EE))
  • The oral estrogenic potency of EC508 in rats is 100 times that of E2 and 10 times that of EE
  • Since EE is typically used at doses of 5 to 50 µg per day, we’d expect EC508 to be effective in even smaller doses
  • A single oral dose of 5.0 mg/kg EC508 in rats resulted in maximal levels of E2 of 6,104,000 pg/mL
  • Since it bypasses the liver, EC508 does not produce excessive levels of estrone or estrone sulfate, unlike oral E2
  • Since it bypasses the liver, oral EC508 does not have disproportionate effects in the liver (for comparison, oral E2 has ~5-fold higher liver potency than parenteral E2, and oral EE ~5-fold that of oral E2—or ~25x parenteral E2)
  • As such, oral EC508 shouldn’t have have the issues with blood clots and cardiovascular events of oral E2 or EE
  • EC508 is under development for use in hormone therapy and birth control pills
  • It has the potential to replace both oral E2 and parenteral E2 in clinical practice
  • EC508 also has the potential to replace EE in birth control pills
  • Unlike earlier compounds like estradiol sulfamate (E2MATE), EC508 is not converted into the corresponding estrone variant and is not thought to be a sulfatase inhibitor, so it should not have the problems that E2MATE had
  • The prodrug approach used to create EC508 has the potential to be used with many other drugs

There is a testosterone equivalent known as EC586 (testosterone 17β-(1-((5-(aminosulfonyl)-2-pyridinyl)carbonyl)-L-proline)) which is under development as well. All of the properties of EC508 are also true for EC586. Hence, EC586 is a highly potent and parenteral-like oral form of testosterone.