Estrogen sulfamates: a new approach to oral estrogen therapy

Abstract

Sulfamate substitution (-O-SO2-NH2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the 'parent' estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At Cmax, approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other 'conventional' estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.

Docking, Synthesis, and in vitro Evaluation of Antimitotic Estrone Analogs

“…The reason for this was ascribed to the bulking of the C-2 position of the estrones (39,40). Also, Elger et al (2001) described how sulfamate substitution at C-3 leads to reduced estrogenic activity when compared to the parent steroids (41). Thus, the ethyl group at C-2 together with the sulfamate group at C-3 of the newly synthesized analogs makes it unlikely that the compounds will have any estrogenic effects.…”

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

“…It was subsequently revealed that earlier studies with N,N-dimethylated sulfamoylated derivatives of estrogens had also shown potent estrogenic properties in rodents but that metabolites of such compounds could accumulate in rbcs. Recent studies have confirmed that estradiol-3-O-sulfamate, the C17-reduced form of EMATE, is also taken up by rbcs and 30 min after administration to rats 98% of the dose is present in rbcs (286). Although some aryl sulfamates, such as 667COUMATE, are relatively unstable when added to plasma ex vivo, they are stabilized in vivo by sequestration into rbcs and binding to CAII (279,287).…”

“…Estradiol-3-O-sulfamate per se does not bind to the ER and therefore acts as a prodrug for the natural estrogen, estradiol (286). On oral application it does not have an estrogenic effect on the liver, indicating that after absorption it must rapidly enter rbcs and transit the liver without undergoing metabolic inactivation.…”

Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential

“…However, the precise mechanism of inhibition is still unknown and other ideas on this subject have been recently discussed [26]. The hydrolysis of EMATE, however, liberates estrone which is estrogenic: the estradiol sulfamate version (E2MATE) behaves similarly with estradiol being liberated which, in rats, resulted in markedly increased systemic (but reduced hepatic) estrogenicity upon oral administration [27] despite the ligand not binding to the estrogen receptor [28]. This occurs as a result of its sequestration and transport through the liver within red blood cells where it is bound to carbonic anhydrase (IC 50 = 23 nM [29]).…”