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Purity: ≥98%
Segesterone acetate (formerly known as ST1435; ST-1435 or nestorone; trade name: Annovera) is a progesterone receptor agonist that is prescribed as a female contraceptive. In August 2018, the FDA approved a novel vaginal ring system that uses estradiol and semen to prevent pregnancy for a full year. Segesterone inhibits proinflammatory mediators and neuropathology in the wobbler mouse model of motoneuron degeneration as a female-contraceptive drug. Segesterone may have benefits for multiple sclerosis (MS) as it prevented hippocampal abnormalities and enhanced the functional outcomes of EAE mice.
| Targets |
progesterone receptor (EC50 = 50.3 nM)
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| ln Vitro |
Segesterone acetate (Nestorone) (20 µM) promotes remyelination of axons by oligodendrocytes after lysolecithin-induced demyelination in organotypic cultures of cerebellar slices from postnatal rats or mice, as shown by increased myelin basic protein (MBP) immunostaining and Western blot analysis.
Segesterone acetate (Nestorone) increases the number of oligodendroglial lineage cells (PLP-EGFP⁺ cells) in demyelinated cerebellar slices. Segesterone acetate (Nestorone) enhances the recruitment of NG2⁺ and Olig2⁺ oligodendrocyte progenitor cells (OPCs) and stimulates their differentiation into mature oligodendrocytes. Segesterone acetate (Nestorone) stimulates the migration of OPCs from brain stem slices into demyelinated cerebellar slices in a coculture system, increasing both the number of migrating EGFP⁺ cells and their migration distance. The proremyelinating effects of Segesterone acetate (Nestorone) are not observed in cerebellar slices from progesterone receptor knockout (PRKO) mice, indicating that its actions are mediated through PR.[2] |
| ln Vivo |
Following Segesterone acetate (400 μCi 3H Nestoron/kg BW; subcutaneous injection; female Sprague-Dawley rats) treatment, the Cmax in plasma and blood is 95.5 and 58.1 ng equiv. 3H Nestoron/g, respectively, with a t1/2 of 15.6 hours. Feces and urine excrete about 81.4% and 7.62% of the dose that was administered, respectively[1].
The study describes the distribution, metabolism, and excretion of Segesterone acetate (Nestorone) following subcutaneous administration in adult female rats. The results are primarily pharmacokinetic and metabolic in nature, not focused on in vivo efficacy or mechanism of action for a therapeutic indication (e.g., contraceptive efficacy).[1] |
| Cell Assay |
Organotypic cerebellar slice cultures were prepared from postnatal day 10 (P10) rats or mice. Slices (350 µm thick) were cultured on microporous membranes in a medium composed of basal medium, Hanks' balanced salt solution, horse serum, L-glutamine, and glucose. After 7 days in vitro (DIV), demyelination was induced by treating slices with lysolecithin (0.5 mg/ml) for approximately 17 hours. The lysolecithin-containing medium was then removed, and slices were incubated for an additional 4 days in medium containing 20 µM Segesterone acetate (Nestorone), progesterone, medroxyprogesterone acetate (MPA), or vehicle control (0.01% ethanol). The medium was replaced once after 2 days.
For coculture experiments, lysolecithin-treated P10 cerebellar slices were transected and apposed to brain stem slices from P0 transgenic mice expressing enhanced green fluorescent protein (EGFP) under the proteolipid gene promoter (PLP-EGFP mice). Cocultures were treated with 20 µM Segesterone acetate (Nestorone) or vehicle for 4 days (medium replaced after 2 days) and analyzed after 10 days for OPC migration. Immunohistochemistry was performed using antibodies against myelin basic protein (MBP), NG2 proteoglycan, Olig2 transcription factor, and Calbindin (Purkinje cell marker). Stained slices were analyzed by confocal microscopy and fluorescence microscopy. MBP staining intensity, number of PLP-EGFP⁺ cells, NG2⁺ cell density, and OPC migration distance were quantified using image analysis software. Western blot analysis was performed on cerebellar slice extracts after lysolecithin treatment and 3-hour incubation with or without 20 µM Segesterone acetate (Nestorone), probing for MBP expression.[2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
In a pharmacokinetic study in healthy women, the contraceptive vaginal ring continuously released a contraceptive dose of segtropone acetate over 90 days. After up to 13 cycles of vaginal administration, segtropone acetate was absorbed into the systemic administration system, reaching peak plasma concentrations within 2 hours in cycles 1, 3, and 13. After reaching peak plasma concentration (Tmax), drug concentrations began to decline and stabilized at 96 hours post-administration. In subsequent cycles, peak serum concentrations of segtropone acetate gradually decreased. Peak plasma concentrations were 1147, 363, and 294 pg/mL in cycles 1, 3, and 13, respectively. In a pharmacokinetic study in rats, approximately 81.4% and 7.62% of the subcutaneously injected dose were excreted in feces and urine, respectively. The volume of distribution of segtropone acetate is 19.6 L/kg. Pharmacokinetic data are unavailable. Metabolism/Metabolites Sigstrosone acetate is rapidly metabolized and inactivated in the liver. Based on in vitro studies, the major oxidative metabolites in serum include 5α-dihydro- and 17α-hydroxy-5α-dihydro metabolites, accounting for approximately 50% of sigstrosone acetate exposure. The metabolites are pharmacologically inactive, with EC50 values for progesterone receptors that are 10 times higher than the parent compound. Studies have shown that 3α,5α-tetrahydrosigstrosone acetate can act as an activator of GABA-A receptors in the brain. Biological Half-Life The mean (standard deviation) half-life of sigstrosone acetate is 4.5 (3.4) hours. Sigstrosone acetate (Nestorone) readily crosses the blood-brain barrier and rapidly diffuses throughout the neural tissue. It has been reported that nestorone acetate may be rapidly metabolized in the liver, which could explain its lack of glucocorticoid-like effects despite its low affinity for glucocorticoid receptors (GR). [2] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation Based on current evidence, US experts believe that postpartum breastfeeding women should not use combined hormonal contraceptives (dHHs) during the first 3 weeks postpartum due to concerns about increased risk of venous thromboembolism (VTE); they should also generally not use DHHs during the 4th week postpartum due to concerns about potential impact on breastfeeding. Postpartum breastfeeding women with other VTE risk factors should generally discontinue DHHs within 6 weeks postpartum. The World Health Organization (WHO) guidelines are more stringent, stating that breastfeeding women should not use DHHs within 42 days postpartum, and that the disadvantages of using this method generally outweigh the benefits during the 6 weeks to 6 months postpartum. Reduced milk production may occur in the first few days after estrogen exposure. ◉ Effects on Breastfed Infants As of the revision date, no published information was found regarding segstrom acetate and ethinylestradiol vaginal suppositories. Studies on the use of segstrom acetate implants have found no adverse effects on growth and development. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Protein binding Segstrone acetate has a serum protein binding rate of approximately 95%, with negligible binding affinity for sex hormone-binding globulin (SHBG). Segstrone acetate (Nestorone) is described as lacking significant androgenic, estrogen-, glucocorticoid-like, or mineralocorticoid-like activity, indicating a favorable side effect profile in the studied cases. |
| References | |
| Additional Infomation |
Pharmacodynamics
Segasterone acetate inhibits ovulation. In a phase I randomized, placebo-controlled, randomized crossover study involving healthy adult female subjects, no clinically significant QTc interval prolongation was observed after a single intravenous injection of segasterone. Segasterone acetate does not possess androgenic, anabolic, or estrogenic activity. It also did not exhibit uterine growth activity in ovariectomized rats. In an endometrial transformation assay assessing progestin activity, a dose-dependent increase in uterine weight was observed after subcutaneous injection of segasterone acetate. Segasterone acetate (Nestorone) is a synthetic 19-norprogesterone derivative, also classified as a fourth-generation progestin. It is designed to be highly selective for the progesterone receptor (PR). In this study, Segasterone acetate (Nestorone) demonstrated potent promyelin regeneration activity by stimulating the recruitment, migration, and differentiation of oligodendrocyte precursor cells (OPCs) (key steps in myelin repair). This effect is dependent on the progesterone receptor (PR), as it was not observed in PR knockout mice. Conversely, another synthetic progesterone, medroxyprogesterone acetate (MPA), did not promote myelin regeneration or oligodendrocyte replenishment in the same model. Nestorone acetate is considered a promising candidate for promoting endogenous myelin repair in demyelinating diseases such as multiple sclerosis due to its selectivity for PR, neuroprotective potential, and ability to modulate key myelin regeneration processes. The authors note that nestorone acetate is currently being tested as a contraceptive and may have therapeutic applications for both male and female patients. This study was funded by a research grant, and several authors are inventors of related patents. [2] |
| Molecular Formula |
C23H30O4
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| Molecular Weight |
370.49
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| Exact Mass |
370.214
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| Elemental Analysis |
C, 74.56; H, 8.16; O, 17.27
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| CAS # |
7759-35-5
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| Related CAS # |
7690-08-6;7759-35-5 (acetate);
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| PubChem CID |
108059
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| Appearance |
White to off-white solid powder
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| Density |
1.15g/cm3
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| Boiling Point |
499.3ºC at 760mmHg
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| Melting Point |
173-177
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| Flash Point |
216.2ºC
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| Index of Refraction |
1.549
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| LogP |
4.185
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
762
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| Defined Atom Stereocenter Count |
6
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| SMILES |
CC([C@]1(OC(C)=O)[C@@]2([C@]([H])([C@@]3(CCC4=CC(CC[C@@]4([C@]3(CC2)[H])[H])=O)[H])CC1=C)C)=O
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| InChi Key |
CKFBRGLGTWAVLG-GOMYTPFNSA-N
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| InChi Code |
InChI=1S/C23H30O4/c1-13-11-21-20-7-5-16-12-17(26)6-8-18(16)19(20)9-10-22(21,4)23(13,14(2)24)27-15(3)25/h12,18-21H,1,5-11H2,2-4H3/t18-,19+,20+,21-,22-,23-/m0/s1
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| Chemical Name |
[(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-16-methylidene-3-oxo-2,6,7,8,9,10,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6991 mL | 13.4956 mL | 26.9913 mL | |
| 5 mM | 0.5398 mL | 2.6991 mL | 5.3983 mL | |
| 10 mM | 0.2699 mL | 1.3496 mL | 2.6991 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04272008 | Completed | Drug: Segesterone Acetate and Ethinyl Estradiol Other: Tampon |
Contraception | TherapeuticsMD | March 6, 2020 | Phase 1 |
| NCT04290390 | Completed | Drug: Segesterone Acetate and Ethinyl Estradiol Drug: Rifampin |
Women Hemodialysis |
TherapeuticsMD | February 12, 2020 | Phase 1 |
COA
