Identification

Name
Ulipristal
Accession Number
DB08867  (DB05366)
Type
Small Molecule
Groups
Approved
Description

Ulipristal is a selective progesterone receptor modulator used for the purposes of emergency contraception (Ella) and for the treatment of uterine fibroids (Fibristal). It is a derivative of 19-norprogesterone and has both antagonistic and partial agonist activity at the progesterone receptor. It also binds to glucocorticoid receptor, however compared to mifepristone (a progesterone receptor antagonist), ulipristal is more tolerable and has lower glucocorticoid activity and better binding affinity.

Ulipristal is currently recommended as first line therapy for emergency contraception, due to improved efficacy and similar side effect profile as compared to the traditional use of levonorgestrel or the Yuzpe regimen. The exact mechanism of action for ulipristal is still currently debated, though there is evidence that it functions by inhibiting ovulation. A recent systematic review proclaimed that the majority of available evidence demonstrates an inhibitory effect on ovulation rather than a post-fertilization effect on the endometrium, which has been heavily debated due to ethical concerns related to abortion (Rosato et al, 2016).

Structure
Thumb
Synonyms
Not Available
External IDs
CDB 2914 / CDB-2914 / CDB2914
Product Ingredients
IngredientUNIICASInChI Key
Ulipristal acetateYF7V70N02B126784-99-4OOLLAFOLCSJHRE-ZHAKMVSLSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EllaTablet30 mgOralLaboratoire HRA Pharma2015-09-01Not applicableCanada
EllaTablet30 mg/1OralActavis Pharma Company2010-08-132013-12-27Us
EllaTablet30 mg/1OralAfaxys Pharma Llc2010-08-13Not applicableUs
EllaTablet30 mg/1OralA-S Medication Solutions2010-08-13Not applicableUs
EllaoneTablet30 mgOralLaboratoire HRA Pharma2009-05-15Not applicableEu
EsmyaTablet5 mgOralGedeon Richter Ltd2012-02-23Not applicableEu
EsmyaTablet5 mgOralGedeon Richter Ltd2012-02-23Not applicableEu
EsmyaTablet5 mgOralGedeon Richter Ltd2012-02-23Not applicableEu
EsmyaTablet5 mgOralGedeon Richter Ltd2012-02-23Not applicableEu
EsmyaTablet5 mgOralGedeon Richter Ltd2012-02-23Not applicableEu
International/Other Brands
EllaOne (HRA Pharma ) / Esmya (Preglen UK )
Categories
UNII
6J5J15Q2X8
CAS number
159811-51-5
Weight
Average: 433.592
Monoisotopic: 433.261693991
Chemical Formula
C28H35NO3
InChI Key
HKDLNTKNLJPAIY-WKWWZUSTSA-N
InChI
InChI=1S/C28H35NO3/c1-17(30)28(32)14-13-25-23-11-7-19-15-21(31)10-12-22(19)26(23)24(16-27(25,28)2)18-5-8-20(9-6-18)29(3)4/h5-6,8-9,15,23-25,32H,7,10-14,16H2,1-4H3/t23-,24+,25-,27-,28-/m0/s1
IUPAC Name
(10S,11S,14R,15S,17R)-14-acetyl-17-[4-(dimethylamino)phenyl]-14-hydroxy-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-1,6-dien-5-one
SMILES
CN(C)C1=CC=C(C=C1)[C@H]1C[C@@]2(C)[C@@H](CC[C@]2(O)C(C)=O)[C@@H]2CCC3=CC(=O)CCC3=C12

Pharmacology

Indication

As the product Ella (available in Canada and the US), ulipristal is indicated for use as emergency contraception after unprotected intercourse or possible contraceptive failure when administered within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure. As the product Fibristal (available in Canada), ulipristal is indicated for treatment of the signs and symptoms of uterine fibroids in adult women.

Associated Conditions
Associated Therapies
Pharmacodynamics

Ulipristal is a selective, reversible progestin receptor modulator and its tissue targets include the uterus, cervix, ovaries, and hypothalamus. Ulipristal may act as an agonist or antagonist in the presence or absence of progesterone based on the tissue target. If given mid-follicular phase, development of the follicle growth is delayed and estradiol concentrations decrease. If given at the time when luteinizing hormone peaks, follicular rapture is delayed by several days. If given early-luteal phase, a decrease in endometrial thickness can be observed.

Mechanism of action

The exact mechanism of action has been heavily debated, although recent evidence suggests that ulipristal functions primarily through inhibition of ovulation, via prevention of progestin binding to the progesterone receptor. In the treatment of fibroids, ulipristal exerts a direct action on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis.

TargetActionsOrganism
AProgesterone receptor
modulator
Human
AGlucocorticoid receptor
antagonist
Human
UAndrogen receptorNot AvailableHuman
Absorption

Tmax, healthy subjects, single oral dose = 60-90 minutes; Cmax, healthy subjects, single oral dose = 176 ± 89 ng/mL; AUC(0-∞), healthy subjects, single oral dose = 556 ± 260 ng·h/mL;

Volume of distribution
Not Available
Protein binding

>94% bound to plasma proteins such as albumin, alpha1-acid glycoprotein, lipoproteins (VLDL, LDL, and HDL- due to its lipophillic nature)

Metabolism

Ulipristal is metabolized by CYP3A4 and to a lesser extent by CYP1A2 into mono-demethylated (active) and di-methylated (inactive) metabolites.

Route of elimination
Not Available
Half life

Mean elimination half-life, single oral dose, healthy subject = 32.4 ± 6.3 hours

Clearance

Mean oral clearance, single oral dose, healthy subject (CL/F) = 76.8 ± 64.0L/h

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Ulipristal can be increased when it is combined with Abiraterone.
Acetyl sulfisoxazoleThe serum concentration of Ulipristal can be increased when it is combined with Acetyl sulfisoxazole.
AlbendazoleThe metabolism of Ulipristal can be decreased when combined with Albendazole.
AlclometasoneThe serum concentration of Alclometasone can be increased when it is combined with Ulipristal.
AlfuzosinThe metabolism of Ulipristal can be decreased when combined with Alfuzosin.
AllylestrenolThe therapeutic efficacy of Allylestrenol can be decreased when used in combination with Ulipristal.
AlprazolamThe metabolism of Alprazolam can be decreased when combined with Ulipristal.
AltrenogestThe therapeutic efficacy of Altrenogest can be decreased when used in combination with Ulipristal.
AmcinonideThe serum concentration of Amcinonide can be increased when it is combined with Ulipristal.
AmiodaroneThe serum concentration of Ulipristal can be increased when it is combined with Amiodarone.
Food Interactions
  • A high fat meal may lower mean Cmax and increase mean AUC(0-∞) but these changes are not clinically significant. Take without regards to meals.

References

General References
  1. Pohl O, Osterloh I, Gotteland JP: Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day. J Clin Pharm Ther. 2013 Aug;38(4):314-20. doi: 10.1111/jcpt.12065. Epub 2013 Apr 3. [PubMed:23550906]
  2. Melis GB, Piras B, Marotto MF, Orru' MM, Maricosu G, Pilloni M, Guerriero S, Angiolucci M, Lello S, Paoletti AM: Pharmacokinetic evaluation of ulipristal acetate for uterine leiomyoma treatment. Expert Opin Drug Metab Toxicol. 2012 Jul;8(7):901-8. doi: 10.1517/17425255.2012.695775. Epub 2012 Jun 10. [PubMed:22681335]
  3. Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14. doi: 10.3109/09513590.2013.774591. [PubMed:23437846]
  4. Martinez AM, Thomas MA: Ulipristal acetate as an emergency contraceptive agent. Expert Opin Pharmacother. 2012 Sep;13(13):1937-42. doi: 10.1517/14656566.2012.705832. Epub 2012 Jul 7. [PubMed:22770536]
  5. Maruo T, Ohara N, Matsuo H, Xu Q, Chen W, Sitruk-Ware R, Johansson ED: Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas. Contraception. 2007 Jun;75(6 Suppl):S99-103. Epub 2007 Mar 21. [PubMed:17531625]
  6. Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, Rosenberg M, Higgins J: Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol. 2006 Nov;108(5):1089-97. [PubMed:17077229]
  7. Blithe DL, Nieman LK, Blye RP, Stratton P, Passaro M: Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids. 2003 Nov;68(10-13):1013-7. [PubMed:14667994]
  8. Attardi BJ, Burgenson J, Hild SA, Reel JR: In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J Steroid Biochem Mol Biol. 2004 Mar;88(3):277-88. [PubMed:15120421]
  9. Rosato E, Farris M, Bastianelli C: Mechanism of Action of Ulipristal Acetate for Emergency Contraception: A Systematic Review. Front Pharmacol. 2016 Jan 12;6:315. doi: 10.3389/fphar.2015.00315. eCollection 2015. [PubMed:26793107]
External Links
KEGG Drug
D09567
PubChem Compound
13559281
PubChem Substance
310264902
ChemSpider
19349271
ChEBI
71025
ChEMBL
CHEMBL2103846
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ulipristal_acetate
ATC Codes
G03AD02 — UlipristalG03XB02 — Ulipristal
AHFS Codes
  • 68:12.00 — Contraceptives
FDA label
Download (309 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0WithdrawnTreatmentUrogenital Abnormalities1
1CompletedBasic ScienceRenal Function1
1CompletedTreatmentHealthy Volunteers1
1Not Yet RecruitingTreatmentHeavy Menstrual Bleeding1
1RecruitingOtherLeiomyomas1
1RecruitingPreventionContraception2
1, 2RecruitingTreatmentOvulation Inhibition1
2CompletedNot AvailableContraception1
2CompletedPreventionFocus: Estrogen-free Oral Contraception1
2CompletedTreatmentContraception1
2CompletedTreatmentLeiomyomas3
2CompletedTreatmentOne to five years postmenopausal1
2Not Yet RecruitingOtherContraception / Healthy Female1
2Not Yet RecruitingPreventionCancer, Breast1
2RecruitingTreatmentEndometriosis of Uterus1
2TerminatedTreatmentCMT1A1
2TerminatedTreatmentDepression / PMDD / Premenstrual Dysphoric Disorder / Premenstrual Syndrome1
2, 3CompletedTreatmentEmergency Contraception1
3CompletedOtherEmergency Contraception1
3CompletedTreatmentContraception1
3CompletedTreatmentContraception / Haemorrhage1
3CompletedTreatmentEmergency Contraception1
3CompletedTreatmentIntramural Fibroids / Uterine Leiomyomas1
3CompletedTreatmentUterine Bleeding in Women With Leiomyomas2
3CompletedTreatmentUterine Leiomyomas6
3WithdrawnTreatmentLeiomyomas1
4Active Not RecruitingBasic ScienceContraception1
4Active Not RecruitingTreatmentEndometriosis1
4Active Not RecruitingTreatmentLeiomyomas1
4Not Yet RecruitingTreatmentUterine Leiomyomas1
4Not Yet RecruitingTreatmentWomen With Leiomyoma After at Least One Unsuccessful IVF Treatment1
4RecruitingBasic ScienceContraception1
4RecruitingPreventionContraception1
4RecruitingTreatmentAbnormal Bleeding / Heavy Menstrual Bleeding1
4RecruitingTreatmentBMI >30 kg/m2 / Contraception1
4RecruitingTreatmentInfertilities1
4RecruitingTreatmentLeiomyomas4
4RecruitingTreatmentUterine Hemorrhage / Uterine Leiomyomas1
4WithdrawnTreatmentDysmenorrhea / Endometriosis of Uterus / Heavy Uterine Bleeding1
Not AvailableActive Not RecruitingNot AvailableFibroid Uterus / Infertility, Female1
Not AvailableCompletedNot AvailableContraception2
Not AvailableCompletedNot AvailableEmergency Contraception1
Not AvailableRecruitingPreventionPregnancy; Accident / Unplanned Pregnancy1
Not AvailableUnknown StatusNot AvailableInfertilities1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral30 mg
TabletOral30 mg/1
TabletOral5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8426392No2010-06-122030-06-12Us
US8962603No2010-06-122030-06-12Us
US9283233No2010-04-132030-04-13Us
US8735380No2009-02-202029-02-20Us
US8512745No2010-06-022030-06-02Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00943 mg/mLALOGPS
logP4.45ALOGPS
logP4.18ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)12.7ChemAxon
pKa (Strongest Basic)4.89ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area57.61 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity129.29 m3·mol-1ChemAxon
Polarizability49.66 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9964
Blood Brain Barrier+0.6396
Caco-2 permeable+0.577
P-glycoprotein substrateSubstrate0.6286
P-glycoprotein inhibitor IInhibitor0.9708
P-glycoprotein inhibitor IIInhibitor0.9321
Renal organic cation transporterNon-inhibitor0.799
CYP450 2C9 substrateNon-substrate0.8337
CYP450 2D6 substrateNon-substrate0.8848
CYP450 3A4 substrateSubstrate0.8312
CYP450 1A2 substrateNon-inhibitor0.5677
CYP450 2C9 inhibitorNon-inhibitor0.7078
CYP450 2D6 inhibitorNon-inhibitor0.7827
CYP450 2C19 inhibitorNon-inhibitor0.6021
CYP450 3A4 inhibitorInhibitor0.7866
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6633
Ames testNon AMES toxic0.8603
CarcinogenicityNon-carcinogens0.7916
BiodegradationNot ready biodegradable0.9933
Rat acute toxicity2.6728 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9538
hERG inhibition (predictor II)Non-inhibitor0.686
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as 20-oxosteroids. These are steroid derivatives carrying a C=O group at the 20-position of the steroid skeleton.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Oxosteroids
Direct Parent
20-oxosteroids
Alternative Parents
3-oxosteroids / 17-hydroxysteroids / Dialkylarylamines / Aniline and substituted anilines / Cyclohexenones / Tertiary alcohols / Alpha-hydroxy ketones / Cyclic alcohols and derivatives / Organopnictogen compounds / Organic oxides
show 1 more
Substituents
20-oxosteroid / 3-oxosteroid / Hydroxysteroid / 17-hydroxysteroid / Tertiary aliphatic/aromatic amine / Aniline or substituted anilines / Dialkylarylamine / Cyclohexenone / Monocyclic benzene moiety / Benzenoid
show 17 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Progesterone receptor
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Modulator
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. Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14. doi: 10.3109/09513590.2013.774591. [PubMed:23437846]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
Molecular Weight
85658.57 Da
References
  1. Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14. doi: 10.3109/09513590.2013.774591. [PubMed:23437846]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14. doi: 10.3109/09513590.2013.774591. [PubMed:23437846]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
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. Gemzell-Danielsson K, Rabe T, Cheng L: Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14. doi: 10.3109/09513590.2013.774591. [PubMed:23437846]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Martinez AM, Thomas MA: Ulipristal acetate as an emergency contraceptive agent. Expert Opin Pharmacother. 2012 Sep;13(13):1937-42. doi: 10.1517/14656566.2012.705832. Epub 2012 Jul 7. [PubMed:22770536]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da

Drug created on April 26, 2013 23:33 / Updated on September 24, 2018 02:41