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Dienogest (formerly BAY86-5258; M-18575; MJR-35; ZK-37659; STS-557; Dinagest; Endometrion; Visanne) is a synthetic and orally bioavailable progesterone that was approved for use in contraception and the treatment of endometriosis. It is available for use as an oral contraceptive in combination with ethinylestradiol. It has antiandrogenic activity and as a result can improve androgenic symptoms. It is a non-ethinylated progestin which is structurally related to testosterone.
Physicochemical Properties
| Molecular Formula | C20H25NO2 | |
| Molecular Weight | 311.42 | |
| Exact Mass | 311.188 | |
| CAS # | 65928-58-7 | |
| Related CAS # | Dienogest-d4;Dienogest-d5;Dienogest-d6 | |
| PubChem CID | 68861 | |
| Appearance | White to light yellow solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 549.0±50.0 °C at 760 mmHg | |
| Melting Point | 210-214ºC | |
| Flash Point | 285.8±30.1 °C | |
| Vapour Pressure | 0.0±3.3 mmHg at 25°C | |
| Index of Refraction | 1.589 | |
| LogP | 1.96 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 1 | |
| Heavy Atom Count | 23 | |
| Complexity | 679 | |
| Defined Atom Stereocenter Count | 4 | |
| SMILES | C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@]2(CC#N)O |
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| InChi Key | AZFLJNIPTRTECV-FUMNGEBKSA-N | |
| InChi Code | InChI=1S/C20H25NO2/c1-19-8-6-16-15-5-3-14(22)12-13(15)2-4-17(16)18(19)7-9-20(19,23)10-11-21/h12,17-18,23H,2-10H2,1H3/t17-,18+,19+,20-/m1/s1 | |
| Chemical Name | 2-((8S,13S,14S,17R)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)acetonitrile | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| ln Vitro | Dienogest (0.01-1 μM; 24 h) decreases PGE2 synthesis by inhibiting PGE2 synthase gene expression and simultaneously inhibits NF-κB activity in spheroid cultures [1]. Dienogest (0.1 μM; 24 h) suppresses the expression of aromatase expression genes and COUP-TFII mRNA in a PGE2-independent manner [1]. |
| ln Vivo | In a rat endometrial autotransplantation model, dienogest (1 mg/kg; orally once daily for 14 days) modulates angiogenesis in ectopic endometrial lesions [2]. |
| Cell Assay |
Cell Viability Assay[1] Cell Types: EM-PR cells Tested Concentrations: 0.01-1 µM Incubation Duration: 24 h Experimental Results: Inhibited PGE2 production and suppressed NF-κB binding activity in the spheroid culture. Cell Viability Assay[1] Cell Types: EM-PR cells Tested Concentrations: 0.1 µM Incubation Duration: 24 h Experimental Results: diminished the mRNA expression of the PGE2 synthases COX-2 and mPGES-1 compared with the respective control. Inhibited aromatase mRNA expression and increased the expression of COUP-TFII mRNA level . |
| Animal Protocol |
Animal/Disease Models: Female Wistar rats (8 to 10weeks old; 180-220 g; rat endometrial autograft model)[2]. Doses: 1 mg/kg Route of Administration: Oral administration; one time/day for 14 days. Experimental Results: demonstrated significant suppression of angiogenesis of endometrial autografts, as indicated by the decreased size of the microvascular network and diminished microvessel density. Dramatically decreased the level of perivascular α-smooth muscle actin within endometrial grafts. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg. The stable concentrations of the drug are reached after two days of initial treatment. The ratio of renal elimination to fecal elimination of dienogest is 3:1, where dienogest is predominantly excreted in the form of inactive metabolites. Most of orally administered drug is excreted in the urine within the first 24 hours of ingestion. The apparent volume of distribution (Vd/F) of dienogest is 40 L. The metabolic clearance rate from serum (Cl/F) is 64 mL/min. Metabolism / Metabolites Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4. The metabolites are pharmacologically inactive and rapidly eliminated from the plasma. Biological Half-Life Elimination half-life of dienogest is around 9-10 hours. The half-life of urinary metabolites excretion is 14 hours. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Dienogest is only available in the United States in a combination oral contraceptive product that also contains estradiol valerate. Based on the available evidence, expert opinion holds that nonhormonal methods are preferred during breastfeeding and progestin-only contraceptives are preferred over combined oral contraceptives in breastfeeding women, especially during the first 4 weeks postpartum. For further information, consult the record entitled, Contraceptives, Oral, Combined. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Dienogest is 90% nonospecifically bound to albumin. It displays no binding to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). |
| References |
[1]. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids. 2011 Jan;76(1-2):60-7. [2]. Effect of dienogest administration on angiogenesis and hemodynamics in a rat endometrial autograft model. Hum Reprod. 2010 Nov;25(11):2851-8. |
| Additional Infomation |
Dienogest is a steroid hormone that is 17beta-hydroxy-3-oxoestra-4,9-diene substituted at position 17 by a cyanomethyl group. Used as an oral contraceptive. It has a role as a synthetic oral contraceptive, a progesterone receptor agonist and a progestin. It is a 17beta-hydroxy steroid, a 3-oxo-Delta(4) steroid, a steroid hormone and an aliphatic nitrile. It derives from a hydride of an estrane. Dienogest is an orally-active semisynthetic progestogen which also possesses the properties of 17α-hydroxyprogesterone. It is a derivative of 19-nortestosterone and has antiandrogenic properties. It is primarily used as a contraceptive in combination with ethinylestradiol, or in other combination form pills approved in United States and Europe however it is not available in the US by itself. In Europe, Australia, Malaysia, Singapore and Japan, dienogest single therapy is an approved treatment for endometriosis to alleviate painful symptoms of endometriosis and reduce endometriotic lesions. Dienogest is commonly marketed as Visanne, Natazia and Qlaira. Dienogest is a Progestin. Dienogest is an orally-active, semisynthetic, fourth generation, nonethinylated progestogen with antiproliferative, antiandrogenic, anti-inflammatory and antiangiogenic activities that is used in hormone therapy and as a female contraceptive. Upon oral administration, dienogest binds intracellular progesterone receptors which then translocate to the nucleus where the drug-receptor complex interacts with progesterone response elements, thus altering the expression of target genes. Dienogest reduces the production of estradiol, prevents ovulation and alters the cervical mucus and endometrium. In addition, dienogest appears to suppress the expression of cell cycle regulator cyclin D1. Altogether, this may prevent the growth of endometrial epithelial cells and may reduce symptoms associated with leiomyoma. Drug Indication Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol. Treatment of endometriosis Mechanism of Action Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism. Pharmacodynamics Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1mg/kg of dienogest also directly inhibits ovulation. In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder. Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ, and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα. It has no glucocorticoid or mineralocorticoid effects. In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.03 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 (8.03 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (8.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2111 mL | 16.0555 mL | 32.1110 mL | |
| 5 mM | 0.6422 mL | 3.2111 mL | 6.4222 mL | |
| 10 mM | 0.3211 mL | 1.6055 mL | 3.2111 mL |