A prodrug design for improved oral absorption and reduced hepatic interaction

Abstract

A series of estradiol-17-β esters of N-(p-sulfomylbenzamide)-amino acids were prepared and evaluated for systemic and hepatic estrogenic activity after oral administration in ovariectomized rats. The alkyl substitution at nitrogen of amino acids such as proline or N-methyl-alanine produced compounds that exhibit potent oral activity. The proline analog (EC508) was further evaluated along with 17β-estradiol (E2) and ethinyl-estradiol (EE) and compared their effects on the uterus, angiotensin and HDL-cholesterol after oral administration to ovariectomized female rats. Orally administered EC508 produced systemic estrogenic activity 10 times greater than EE and a 100 times higher activity than E2 with no influence on levels of angiotensin and HDL-cholesterol, whereas EE and E2 reduced the HDL-cholesterol and increased the angiotensine plasma levels. EC508 might offer significant advantages in indications like fertility control and HRT based on its high oral bioavailability and lack of hepatic estrogenicity.

Keywords: Estradiol; Estradiol sulfonamide ester; Hepatic estrogenicity; Prodrug; Testosterone.