FDA 4/15/2021, To prevent pregnancy, Nextstellis
New Drug Application (NDA): 214154
Company: MAYNE PHARMA
Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol.
Fishman J., Guzik H., J. Org. Chem. 33, 3133 – 3135 (1968) discloses a successful synthesis of estetrol from an estrone derivative (compound (III); cf. for a synthesis of compound (III) Cantrall, E.W., Littell, R., Bernstein, S. J. Org. Chem 29, 214 – 217 (1964)). In a first step, the carbonyl group at C17 of compound (III) was reduced with LiAlH4 to estra-1,3,5(10),15-tetraene-3,17-diol (compound VIa) that was isolated as the diacetate (compound VIb). Compound VIb was subjected to cis-hydroxylation of the double bond of ring D by using OsO4 which resulted into the formation of estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound Ib) that under heating with K2CO3 in methanol produces estetrol (Scheme 1).
The overall yield of this three step process is, starting from estrone derivative III, only about 7%. It is worth noting that the protected derivative 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IV) could be cis-hydroxylated to its 15α,16α-diol derivative (compound Va), but that thereafter the dioxolane group could not be removed (p-toluene sulfonic acid in acetone at room temperature) or that the hydrolysis (aqueous sulfuric acid in warm dioxane) of the dioxolane group resulted in a mixture containing a multitude of products (Scheme 2).
Suzuki E. et al., Steroids 60, 277 – 284 (1995) also discloses the synthesis of estetrol by using compound Vb of Nambara T. et al. as starting material. The carbonyl group at C17 of this compound was first reduced followed by acetylation yielding estra-1,3,5(10),15-tetraene-3,17-diol-3,17-diacetate (compound 2b). The latter was subjected to oxidation with OsO4 which provided estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound 3b) in 46% yield.
Poirier D., et al., Tetrahedron 47, 7751 – 7766 (1991) discloses the following compounds which were prepared according to methods that have been used to prepare similar compounds:
Example 7 3-Benzyloxy-estra-1,3,5 (10),15-tetraen-17-ol (compound 5; A = benzyl)
Example 8 17-Acetyloxy-3-benzyloxy-estra-1,3,5 (10),15-tetraene (compound 4; A = benzyl, C = acetyl)
Example 9 17-Acetyl-3-Benzyl estetrol (compound 3; A = benzyl, C = acetyl)
Example 10 17-Acetyl estetrol (compound 2; C = acetyl)
Example 11 Estetrol
Estetrol (E4), or oestetrol, is a weak estrogen steroid hormone, which is found in detectable levels only during pregnancy in humans. It is produced exclusively by the fetal liver. Estetrol is closely related to estriol (E3), which is also a weak estrogen that is found in high quantities only during pregnancy. Along with estradiol (E2), estrone (E1), and E3, estetrol (E4) is a major estrogen in the body, although only during pregnancy.
In addition to its role as a natural hormone, estetrol is under clinical development for use as a medication, for instance in hormonal contraception (in combination with drospirenone) and as menopausal hormone therapy; for information on estetrol as a medication, see the estetrol (medication) article.
Estetrol is an estrogen and has estrogenic effects in various tissues. Estetrol interacts with nuclear Estrogen Receptor (ERα) in a manner identical to that of the other estrogens and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs). So far the physiological function of estetrol is unknown. The possible use of estetrol as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal estetrol plasma levels during pregnancy this appeared not to be feasible.
Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen. It has moderate affinity for ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively. As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ. The estrogen has low affinity for the ERs relative to estradiol, and both estetrol and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects to estradiol. The affinity of estetrol for the ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol. Estetrol shows high selectivity for the ERs.
Estetrol is synthesized during pregnancy only in the fetal liver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase. Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step. It appears in maternal urine at around week 9 of pregnancy. After birth the neonatal liver rapidly loses its capacity to synthesize estetrol because these two enzymes are no longer expressed.
Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine. During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy.
Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is a naturally occurring estrane steroid and derivative of estrin (estratriene). It has four hydroxyl groups, which explains the abbreviation E4.
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|Preferred IUPAC name
Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
3D model (JSmol)
CompTox Dashboard (EPA)
|Molar mass||304.386 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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