Estrone sulfamate (EMATE; developmental code name J994), or estrone-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which has not yet been marketed.[1][2][3] It is the C3 sulfamate ester of the estrogen estrone.[1][2] Unlike other estrogen esters however, EMATE is not an effective prodrug of estrogens.[4] A closely related compound is estradiol sulfamate (E2MATE), which is extensively metabolized into EMATE and has similar properties to it.[1][2][3]
EMATE shows high bioavailability and undergoes little or no first-pass metabolism with oral administration.[1][2] The sulfamate moiety of EMATE results in carbonic anhydrase binding which, in turn, results in EMATE being taken up into and stored in erythrocytes in the blood.[1][2] Since this occurs in the hepatic portal vein, it prevents EMATE from entering the liver during the first pass with the oral route.[1][2] The inhibition of STS by EMATE prevents its bioactivation into estrone and estradiol, which in turn accounts for the lack of estrogenicity of EMATE.[4] A short initial peak of estradiol and estrone levels was observed with E2MATE at the start of treatment in humans, followed by very high and long-lasting concentrations of EMATE and estrone sulfate in erythrocytes, observations that are in accordance with STS inhibition.[4]
EMATE is an extremely potent and irreversible inhibitor of STS.[5] It was found to have an IC50Tooltip half-maximal inhibitory concentration of 65 pM for STS inhibition in MCF-7 cells, with an almost complete inhibition of the hydrolysis of physiological concentrations of the steroid sulfates estrone sulfate and dehydroepiandrosterone sulfate in MCF-7 cells observed at a concentration of 1 μM.[5] At a dosage of 1 mg/kg orally or subcutaneously in rats, it effectively abolished estrone and DHEA-S sulfatase activities in all tissues assessed.[5] It also showed a prolonged duration of action, with only a small recovery (<10%) of hepatic STS activity occurring 7 days after a single 10 mg/kg dose in rats.[5]
Due to its ability to prevent the conversion of hormonally inactive steroid sulfates into their hormonally active forms (e.g., estrone sulfate into estrone), STS inhibitors like EMATE have potential applications in the treatment of estrogen-dependent conditions like estrogen receptor-positive breast cancer and endometriosis.[1][2] However, estrogenicity was paradoxically observed with EMATE in rodents, and this resulted in clinical development of the compound not being pursued.[1][2] However, E2MATE was investigated as an estradiol prodrug with improved oral pharmacokinetics and little or no first-pass hepatic impact in humans, but was found to completely lack estrogenic effects.[4] Following this, E2MATE was repurposed as an STS inhibitor, and is now under development for the treatment of endometriosis.[6]
^ abcdefghElger W, Barth A, Hedden A, Reddersen G, Ritter P, Schneider B, et al. (2001). "Estrogen sulfamates: a new approach to oral estrogen therapy". Reproduction, Fertility, and Development. 13 (4): 297–305. doi:10.1071/rd01029. PMID 11800168.
^ abcdefghThomas MP, Potter BV (September 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. PMID 25843211. S2CID 24116740.
^ abElger W, Schwarz S, Hedden A, Reddersen G, Schneider B (December 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. PMID 8541236. S2CID 31312.
^ abcdElger W, Wyrwa R, Ahmed G, Meece F, Nair HB, Santhamma B, et al. (January 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 (Pt B): 305–311. doi:10.1016/j.jsbmb.2016.07.008. PMID 27449818. S2CID 26650319.
^ abcdReed MJ, Purohit A (6 December 2012). "Pharmacology of Inhibition of Estrogen-Metabolizing Enzymes". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 233–239. ISBN 978-3-642-60107-1.
Estronesulfamate (EMATE; developmental code name J994), or estrone-3-O-sulfamate, is a steroid sulfatase (STS) inhibitor which has not yet been marketed...
synthesized as an STS inhibitor along with its oxidized version estrone 3-O-sulfamate (EMATE) in the group of Professor Barry V L Potter at the University...
formation of androstenedione, which is then converted by aromatase into estrone and is subsequently converted into estradiol. Alternatively, androstenedione...
estrone and 65% into estrone sulfate. About 5% of estrone and 1.4% of estrone sulfate is converted back into estradiol. An additional 21% of estrone sulfate...
such as estradiol sulfamate, estronesulfamate, irosustat, and danazol inhibit the conversion of steroid sulfates such as estrone sulfate and DHEA sulfate...
Estriol sulfamate (developmental code name J1034), or estriol 3-O-sulfamate, is a synthetic estrogen and estrogen ester which was never marketed. It is...
of approximately 53% sodium estrone sulfate and 25% sodium equilin sulfate, while EEs contain about 75 to 85% sodium estrone sulfate and 6 to 11% sodium...
irosustat, estronesulfamate (EMATE), estradiol sulfamate (E2MATE), and danazol. The most potent inhibitors are based around the aryl sulfamate pharmacophore...
addition, it was found that E2MATE was substantially transformed into estronesulfamate (EMATE) in erythrocytes, which may have further impeded its capacity...
Ethinylestradiol sulfamate (developmental code name J1028), or 17α-ethynylestradiol 3-O-sulfamate, is a synthetic estrogen and estrogen ester which was...
three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most...
estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification...
mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural...
(17β-HSD). As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the...
dose of estradiol is absorbed 15% as estrone, 25% as estrone sulfate, 25% as estradiol glucuronide, and 25% as estrone glucuronide. Formation of estrogen...
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...
to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration...
continuous 0.25 mg/day oral therapy, and to have a much higher estradiol-to-estrone ratio than oral estradiol of about 2:1. It is thought that this is due...
in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which...
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