Identification

Name
Dienogest
Accession Number
DB09123
Type
Small Molecule
Groups
Approved
Description

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 [1]. Dienogest is commonly marketed as Visanne, Natazia and Qlaira.

Structure
Thumb
Synonyms
  • 17-alpha-Cyanomethyl-17-beta-hydroxy-estra-4,9(10)-dien-3-one
  • 17alpha-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile
  • Dienogest
  • Dienogestril
  • Dienogestum
  • Endometrion
External IDs
BAY 86-5258 / M 18575 / MJR-35 / STS 557 / ZK 37659
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VisanneTablet2.00 mgOralBayer2011-10-25Not applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Estradiol Valerate and Estradiol Valerate/DienogestDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitSandoz2015-08-05Not applicableUs
Estradiol Valerate and Estradiol Valerate/DienogestDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitSandoz2015-08-05Not applicableUs
NataziaDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitPhysicians Total Care, Inc.2010-09-29Not applicableUs54868 618320180113 27003 1ygc4or
NataziaDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitBayer HealthCare Pharmaceuticals Inc.2010-05-06Not applicableUs50419 0409 01 nlmimage10 b219590a
NataziaDienogest (2 mg) + Dienogest (3 mg) + Estradiol valerate (1 mg) + Estradiol valerate (2 mg) + Estradiol valerate (2 mg) + Estradiol valerate (3 mg)TabletOralBayerNot applicableNot applicableCanada
NataziaDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitBayer HealthCare Pharmaceuticals Inc.2010-05-06Not applicableUs50419 0409 01 nlmimage10 b219590a
NataziaDienogest (2 mg/1) + Dienogest (3 mg/1) + Estradiol valerate (3 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (2 mg/1) + Estradiol valerate (1 mg/1)KitPhysicians Total Care, Inc.2010-09-29Not applicableUs54868 618320180113 27003 1ygc4or
NataziaDienogest (2 mg) + Dienogest (3 mg) + Estradiol valerate (1 mg) + Estradiol valerate (2 mg) + Estradiol valerate (2 mg) + Estradiol valerate (3 mg)TabletOralBayerNot applicableNot applicableCanada
Categories
UNII
46M3EV8HHE
CAS number
65928-58-7
Weight
Average: 311.425
Monoisotopic: 311.188529049
Chemical Formula
C20H25NO2
InChI Key
AZFLJNIPTRTECV-FUMNGEBKSA-N
InChI
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
IUPAC Name
2-[(10S,11S,14R,15S)-14-hydroxy-15-methyl-5-oxotetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-1,6-dien-14-yl]acetonitrile
SMILES
[H][C@@]12CC[C@@](O)(CC#N)[C@@]1(C)CCC1=C3CCC(=O)C=C3CC[C@@]21[H]

Pharmacology

Indication

Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol.

Associated Conditions
Associated Therapies
Pharmacodynamics

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use [2] . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate [4]. 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 [2]. In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder [1]. Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ [A16570], and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα [3]. 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 [2].

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 [2]. 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 [5]. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue [4]. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

TargetActionsOrganism
AProgesterone receptor
agonist
Human
AAndrogen receptor
antagonist
Human
Absorption

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 [4]. The stable concentrations of the drug are reached after two days of initial treatment [2].

Volume of distribution

The apparent volume of distribution (Vd/F) of dienogest is 40 L [4].

Protein binding

Dienogest is 90% nonospecifically bound to albumin. It displays no binding to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG) [4].

Metabolism

Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4. The metabolites are pharmacologically inactive and rapidly eliminated from the plasma.

Route of elimination

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 [4].

Half life

Elimination half-life of dienogest is around 9-10 hours. The half-life of urinary metabolites excretion is 14 hours [4].

Clearance

The metabolic clearance rate from serum (Cl/F) is 64 mL/min [4].

Toxicity

Oral LD50 in mouse is 4 mg/kg [MSDS]. In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma [5]. These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity [5]. Dienogest does not display genotoxic potential.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinDienogest may decrease the anticoagulant activities of (R)-warfarin.
(S)-WarfarinDienogest may decrease the anticoagulant activities of (S)-Warfarin.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Dienogest.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Dienogest.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dienogest.
5-androstenedioneThe metabolism of Dienogest can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Dienogest can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Dienogest.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Dienogest.
AbacavirAbacavir may decrease the excretion rate of Dienogest which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Schindler AE: Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175-84. doi: 10.2147/IJWH.S5633. Epub 2011 Jul 6. [PubMed:21792339]
  2. Binkowska M, Woron J: Progestogens in menopausal hormone therapy. Prz Menopauzalny. 2015 Jun;14(2):134-43. doi: 10.5114/pm.2015.52154. Epub 2015 Jun 22. [PubMed:26327902]
  3. Hayashi A, Tanabe A, Kawabe S, Hayashi M, Yuguchi H, Yamashita Y, Okuda K, Ohmichi M: Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis. J Ovarian Res. 2012 Nov 1;5(1):31. doi: 10.1186/1757-2215-5-31. [PubMed:23113924]
  4. Bayer Inc: VISANNE (2mg dienogest tablets) Product Monograph [Link]
  5. Bayer Inc: VISANNE (2mg dienogest tablets) Product Information [Link]
External Links
PubChem Compound
68861
PubChem Substance
310265039
ChemSpider
62093
ChEBI
70708
ChEMBL
CHEMBL1201864
Wikipedia
Dienogest
ATC Codes
G03AB08 — Dienogest and estradiolG03DB08 — DienogestG03FA15 — Dienogest and estrogenG03AA16 — Dienogest and ethinylestradiol
AHFS Codes
  • 68:32.00 — Progestins
MSDS
Download (24.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherBiological Availability1
1CompletedNot AvailableContraception / Oral Contraceptives (OC) / Ovulation Inhibition / Pharmacology, Clinical1
1CompletedNot AvailablePharmacodynamics1
2CompletedTreatmentEndometriosis1
2RecruitingTreatmentAnorexia Nervosa (AN)1
2WithdrawnPreventionEndometriosis / Ovarian Reserve1
2, 3SuspendedTreatmentEndometriosis1
3CompletedPreventionOral Contraceptives (OC)1
3CompletedTreatmentContraception1
3CompletedTreatmentEndometriosis4
3CompletedTreatmentMetrorrhagia3
3CompletedTreatmentPrimary Dysmenorrhoea1
3RecruitingTreatmentPremenstrual Syndrome1
4CompletedOtherContraception1
4Not Yet RecruitingTreatmentEndometriosis of Uterus1
4Not Yet RecruitingTreatmentUterine Leiomyomas1
4RecruitingPreventionEndometriosis1
4RecruitingTreatmentInfertilities1
4Unknown StatusTreatmentUterine Leiomyomas1
Not AvailableActive Not RecruitingNot AvailableEndometriosis1
Not AvailableActive Not RecruitingTreatmentEndometriosis / Infertilities1
Not AvailableCompletedNot AvailableEndometriosis2
Not AvailableNot Yet RecruitingNot AvailableHypermenorrhea1
Not AvailableRecruitingTreatmentEndometriosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Kit
TabletOral
TabletOral2.00 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6133251No2000-10-172016-10-25Us
US8071577No2011-12-062026-05-13Us
US8153616No2012-04-102028-01-30Us
US6884793No2005-04-262016-10-25Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)210-218Bayer Product Monograph
water solubilityPractically insolubleBayer Product Monograph
Predicted Properties
PropertyValueSource
Water Solubility0.0761 mg/mLALOGPS
logP3.37ALOGPS
logP2.31ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)13.78ChemAxon
pKa (Strongest Basic)-3.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area61.09 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity90.19 m3·mol-1ChemAxon
Polarizability35.4 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-03di-0019000000-8b6511db078a7ef4a6d7
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0006-0093000000-b1ea74e40f8e85986825
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0006-0390000000-58a5bd49692ab6bd5ef9
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00dl-0950000000-d53345d5771b7bff2bae
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00di-0910000000-6c64873dce18fb49e840
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00di-1910000000-5dd58f138435ec0555a4
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0009000000-f354babe14ff8cd78da5
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0109000000-aa4e4dd10536f9ed7fb4
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0924000000-0a4b5e59ffb5fd090a1a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0btl-1910000000-baa05a6be42e71aa9634
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0a4u-2900000000-d615a57fc7b003b3df8d
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-05ox-3900000000-17cbf8436dfbbec977c2

Taxonomy

Description
This compound belongs to the class of organic compounds known as oxosteroids. These are steroid derivatives carrying a C=O group attached to steroid skeleton.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Oxosteroids
Direct Parent
Oxosteroids
Alternative Parents
3-oxosteroids / 17-hydroxysteroids / Cyclohexenones / Tertiary alcohols / Cyclic alcohols and derivatives / Nitriles / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
3-oxosteroid / Hydroxysteroid / 17-hydroxysteroid / Oxosteroid / Cyclohexenone / Cyclic alcohol / Tertiary alcohol / Ketone / Cyclic ketone / Carbonitrile
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
aliphatic nitrile, 3-oxo Delta(4)-steroid, 17beta-hydroxy steroid, steroid hormone (CHEBI:70708)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor ...
Gene Name
PGR
Uniprot ID
P06401
Uniprot Name
Progesterone receptor
Molecular Weight
98979.96 Da
References
  1. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. [PubMed:18061638]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...
Gene Name
AR
Uniprot ID
P10275
Uniprot Name
Androgen receptor
Molecular Weight
98987.9 Da
References
  1. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. [PubMed:18061638]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Binkowska M, Woron J: Progestogens in menopausal hormone therapy. Prz Menopauzalny. 2015 Jun;14(2):134-43. doi: 10.5114/pm.2015.52154. Epub 2015 Jun 22. [PubMed:26327902]
  2. Bayer Inc: VISANNE (2mg dienogest tablets) Product Monograph [Link]

Drug created on September 23, 2015 10:17 / Updated on December 14, 2018 17:12