Ulipristal
Overview
Description
Ulipristal is a selective progesterone receptor modulator used primarily for emergency contraception and the treatment of uterine fibroids. It is a derivative of 19-norprogesterone and exhibits both antagonistic and partial agonist activity at the progesterone receptor .
Scientific Research Applications
Ulipristal has a wide range of scientific research applications:
Chemistry: Used as a model compound to study selective progesterone receptor modulators.
Biology: Investigated for its effects on cellular pathways and receptor binding.
Medicine: Primarily used for emergency contraception and the treatment of uterine fibroids.
Industry: Utilized in the pharmaceutical industry for the development of contraceptive pills and fibroid treatments .
Mechanism of Action
Target of Action
Ulipristal is a selective progesterone receptor modulator . It has both antagonistic and partial agonist activity at the progesterone receptor . It also binds to the glucocorticoid receptor .
Mode of Action
This compound works by binding to the body’s progesterone receptors to produce an anti-progesterone effect . This interaction suppresses or delays ovulation from the ovary . It prevents progestin from binding to the progesterone receptor , thereby inhibiting or delaying ovulation . It may also alter the normal endometrium, impairing implantation .
Biochemical Pathways
The exact mechanism of action for this compound is still currently debated, though there is evidence that it functions by inhibiting ovulation . Some studies suggest that this compound may elicit activity on the endometrium that prevents embryo implantation .
Pharmacokinetics
This compound acetate has good oral bioavailability and a half-life allowing one single oral administration per day for the management of fibroids . Following oral administration of a single 30 mg dose, this compound acetate is rapidly absorbed, with a peak plasma concentration occurring approximately 1 hour after ingestion .
Result of Action
The administration of this compound produces a significant decrease in the number of conceptuses compared to control . It also produces histological and functional alterations in the uterine horns, i.e., a dyssynchronous growth between endometrial glands and stroma . It impairs the ability of the uterine horns to respond to an artificial decidualization stimulus .
Action Environment
The action of this compound can be influenced by environmental factors such as the presence of other drugs. For example, the oral coadministration of UPA and ketoconazole reduced UPA metabolism and resulted in an approximate 2-fold increase in the average maximum plasma UPA levels and an approximate average 5.8-fold increase in bioavailability .
Biochemical Analysis
Biochemical Properties
Ulipristal plays a significant role in biochemical reactions by interacting with various enzymes, proteins, and other biomolecules. It binds to the progesterone receptor, exhibiting both antagonistic and partial agonist activities. Additionally, this compound binds to the glucocorticoid receptor, although it has lower glucocorticoid activity compared to mifepristone . These interactions are crucial for its function as an emergency contraceptive and in the treatment of uterine fibroids.
Cellular Effects
This compound affects various types of cells and cellular processes. In the treatment of uterine fibroids, this compound reduces the size of fibroids by inhibiting cell proliferation and inducing apoptosis . It also influences cell signaling pathways, gene expression, and cellular metabolism. For instance, this compound has been shown to delay or inhibit ovulation by affecting the endometrium, which may prevent embryo implantation .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to the progesterone receptor, where it acts as both an antagonist and partial agonist . This binding prevents progestin from binding to the receptor, thereby inhibiting or delaying ovulation . This compound also alters the normal endometrium, impairing implantation . Additionally, it inhibits the translocation of the glucocorticoid receptor to the nucleus, affecting gene expression .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound change over time. This compound is rapidly absorbed, with a peak plasma concentration occurring approximately one hour after ingestion . Its stability and degradation over time have been studied, showing that it can inhibit follicular rupture and induce early endometrial bleeding in a dose-dependent manner . Long-term effects on cellular function have also been observed, including changes in endometrial maturation and progesterone-dependent markers of implantation .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. A single post-ovulatory dose of this compound has been shown to impair post-fertilization events in mice, reducing the number of conceptuses and early implantation sites . High doses of this compound can cause histological and functional alterations in the uterine horns, affecting embryo-uterine interaction .
Metabolic Pathways
This compound is metabolized primarily by the enzyme CYP3A4 and to a lesser extent by CYP1A2 . It is converted into mono-demethylated (active) and di-methylated (inactive) metabolites . These metabolic pathways are crucial for its pharmacokinetics and overall efficacy.
Transport and Distribution
This compound is transported and distributed within cells and tissues, targeting the uterus, cervix, ovaries, and hypothalamus . It binds to plasma proteins with a high affinity, which influences its distribution and localization within the body . The transporters and binding proteins involved in its distribution play a significant role in its therapeutic effects.
Subcellular Localization
The subcellular localization of this compound involves its interaction with the glucocorticoid receptor, where it inhibits the receptor’s translocation to the nucleus . This inhibition affects the receptor’s activity and function, leading to changes in gene expression and cellular responses. This compound’s targeting signals and post-translational modifications direct it to specific compartments or organelles, influencing its overall activity.
Preparation Methods
Synthetic Routes and Reaction Conditions
The synthesis of ulipristal involves multiple steps, starting from 19-norprogesteroneThe reaction conditions typically involve the use of reagents such as methyl lithium or methyl Grignard reagent for the addition reactions, followed by hydrolysis and crystallization steps to purify the final product .
Industrial Production Methods
Industrial production of this compound involves optimizing the synthetic route to ensure high yield and purity. This includes controlling the hydrolysis conditions such as acidity, temperature, and reaction time to obtain the desired product. The final product is purified using solvents like ethanol and isopropanol .
Chemical Reactions Analysis
Types of Reactions
Ulipristal undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized to form different metabolites.
Reduction: Reduction reactions can modify the ketone groups present in the molecule.
Substitution: Substitution reactions can occur at the dimethylamino group or the acetoxy group.
Common Reagents and Conditions
Common reagents used in these reactions include oxidizing agents like potassium permanganate and reducing agents like sodium borohydride. The reactions are typically carried out under controlled temperature and pH conditions to ensure the desired product formation .
Major Products Formed
The major products formed from these reactions include various metabolites that retain the core structure of this compound but with modifications at specific functional groups .
Comparison with Similar Compounds
Similar Compounds
Mifepristone: Another progesterone receptor antagonist used for medical abortion and emergency contraception.
Levonorgestrel: A synthetic progestogen used in emergency contraception and hormonal contraceptives.
Uniqueness of Ulipristal
This compound is unique in its dual activity as both an antagonist and partial agonist at the progesterone receptor, which provides it with a distinct efficacy and side effect profile compared to other compounds like mifepristone and levonorgestrel .
Properties
IUPAC Name |
(8S,11R,13S,14S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
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 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
HKDLNTKNLJPAIY-WKWWZUSTSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(=O)C1(CCC2C1(CC(C3=C4CCC(=O)C=C4CCC23)C5=CC=C(C=C5)N(C)C)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC(=O)[C@]1(CC[C@@H]2[C@@]1(C[C@@H](C3=C4CCC(=O)C=C4CC[C@@H]23)C5=CC=C(C=C5)N(C)C)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C28H35NO3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID501025842 |
Source
|
| Record name | Ulipristal | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501025842 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
433.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
The exact mechanism of action of ulipristal has been heavily debated. On one hand, the majority of official prescribing information labels, monographs, and prior research studies for ulipristal indicated as an emergency contraceptive suggest that its primary mechanism of action revolves around inhibiting or delaying ovulation by suppressing surges in LH that result in the postponement of follicular rupture. Conversely, some of the latest investigations pertaining to ulipristal's mechanism of action as an emergency contraceptive propose that it principally elicits its action by preventing embryo implantation, as opposed to preventing ovulation. Although previous investigations have shown that ulipristal essentially has the ability to prevent ovulation equivalent to placebo (ie. null effect or ability) when administered during LH peaks one to two days before ovulation, the agent still demonstrates a stable and consistently high contraceptive effect of approximately >=80% when used at this time. Subsequently, current studies attempt to investigate how ulipristal could elicit emergency contraception via ovulation prevention under circumstances where ovulation had already clearly been observed. Endometrial biopsy samples studied from such circumstances in such investigations subsequently show that the administered ulipristal causes endometrial tissue to become inhospitable and unsuitable for embryo implantation where a variety of genes characteristic of receptive, pro-gestational endometrium are downregulated. Nevertheless, most if not all proposed mechanisms commonly agree that ulipristal ultimately demonstrates its pharmacological effects by binding to human progesterone receptors and prevents natural, endogenous progesterone from occupying such receptors. Regardless, however, considering current and on-going research into ulipristal's ability to prevent embryo implantation, the notion that the medication can elicit post-fertilization effects potentially raises alerts and/or ethical debates over the use of ulipristal owing to potential abortifacient activity, which is considered to be on par or equipotent to that of mifepristone. Attention should be drawn to the fact that some prescribing information, however, such as the US FDA label for ulipristal indicated for emergency contraception, has included new supplementary commentary since 2018 that directly warns about ulipristal not being indicated for termination of existing pregnancies and suggesting that ulipristal use may confer alterations to the endometrium that may affect implantation and contribute to efficacy. In the treatment of fibroids, ulipristal has been shown to exert direct actions on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis. |
Source
|
| Record name | Ulipristal | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08867 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
159811-51-5 |
Source
|
| Record name | Ulipristal [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0159811515 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Ulipristal | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08867 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Ulipristal | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501025842 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | (8S,11R,13S,14S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | ULIPRISTAL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6J5J15Q2X8 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Retrosynthesis Analysis
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