Estrone sulfamate (EMATE; developmental code name J994), or estrone-3-''O''-sulfamate, is a

steroid sulfatase Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalysis, catalyses the follow ...

(STS)

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

which has not yet been marketed. It is the C3

sulfamate Sulfamic acid, also known as amidosulfonic acid, amidosulfuric acid, aminosulfonic acid, sulphamic acid and sulfamidic acid, is a molecular compound with the formula H3NSO3. This colourless, water-soluble compound finds many applications. Sulfami ...

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

of the

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

estrone. Unlike other

estrogen ester An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol ...

s however, EMATE is not an effective

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

of estrogens. A closely related compound is estradiol sulfamate (E2MATE), which is extensively

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

into EMATE and has similar properties to it. EMATE shows high bioavailability and undergoes little or no first-pass metabolism with

oral administration Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

. The sulfamate

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

of EMATE results in

carbonic anhydrase The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). The active site ...

binding which, in turn, results in EMATE being taken up into and stored in

erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

. Since this occurs in the

hepatic portal vein The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...

, it prevents EMATE from entering the liver during the first pass with the oral route. The inhibition of STS by EMATE prevents its

bioactivation Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction. Chemistry In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...

into estrone and estradiol, which in turn accounts for the lack of estrogenicity of EMATE. 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

s, observations that are in accordance with STS inhibition. EMATE is an extremely potent and irreversible inhibitor of STS. It was found to have an of 65 pM for STS inhibition in MCF-7 cells, with an almost complete inhibition of the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of physiological concentrations of the

steroid sulfate Steroid sulfates are endogenous sulfate esters of steroids. They are formed by steroid sulfotransferases via sulfation of endogenous steroids like cholesterol and steroid hormones. Although steroid sulfates do not bind to steroid hormone receptor ...

s estrone sulfate and

dehydroepiandrosterone sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepi ...

in MCF-7 cells observed at a concentration of 1 μM. 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. It also showed a prolonged

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...

, with only a small recovery (<10%) of

hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

STS activity occurring 7 days after a single 10 mg/kg dose in rats. Due to its ability to prevent the

conversion Conversion or convert may refer to: Arts, entertainment, and media * "Conversion" (''Doctor Who'' audio), an episode of the audio drama ''Cyberman'' * "Conversion" (''Stargate Atlantis''), an episode of the television series * "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 condition An estrogen-dependent condition can be that relating to the differentiation in the steroid sex hormone that is associated with the female reproductive system and sex characteristics. These conditions can fall under the umbrella of hypoestrogenism, h ...

s like estrogen receptor-positive

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

and

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

. However, estrogenicity was paradoxically observed with EMATE in rodents, and this resulted in clinical development of the compound not being pursued. However, E2MATE was investigated as an estradiol prodrug with improved oral

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

and little or no first-pass hepatic impact in humans, but was found to completely lack estrogenic effects. Following this, E2MATE was repurposed as an STS inhibitor, and is now under development for the treatment of endometriosis.

References

{{Estrogen receptor modulators Abandoned drugs Estrone esters Ketones Steroid sulfatase inhibitors Sulfamate esters

See also

References