Ulipristal

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 .

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 .

Emergency Contraception

Mechanism of Action
Ulipristal is primarily utilized as an emergency contraceptive (marketed as Ella) and is effective when administered within 120 hours (5 days) after unprotected intercourse. Its mechanism involves delaying or inhibiting ovulation by suppressing luteinizing hormone surges, thus preventing follicular rupture. There is ongoing debate regarding its potential effects on the endometrium, with some studies suggesting it may alter endometrial receptivity .

Efficacy
this compound acetate has been shown to be more effective than levonorgestrel, particularly when taken within the first 24 hours after unprotected intercourse. A systematic review indicated that this compound reduced unplanned pregnancies by approximately two-thirds compared to levonorgestrel . The following table summarizes the efficacy of this compound compared to levonorgestrel:

Case Studies
A multicenter study involving over 2,000 women demonstrated that this compound had a pregnancy rate of only 1.9%, significantly lower than the expected rate of 5.5% . This efficacy was consistent across various demographics, although higher pregnancy rates were noted among obese women who engaged in further acts of unprotected intercourse .

Treatment of Uterine Fibroids

Indications and Mechanism
this compound is also indicated for the treatment of uterine fibroids (marketed as Fibristal). It works by modulating progesterone receptors in uterine tissue, leading to a reduction in fibroid size and alleviation of associated symptoms such as heavy menstrual bleeding and pelvic pain .

Clinical Trials
Several clinical trials have evaluated the safety and efficacy of this compound in managing uterine fibroids. In one Phase III study, this compound significantly reduced fibroid volume and improved quality of life measures among women with symptomatic uterine fibroids .

Data Table: Clinical Trial Outcomes

Ulipristal exerts its effects by binding to the progesterone receptor, where it acts as both an antagonist and partial agonist. This binding inhibits ovulation by preventing follicular rupture and may also affect the endometrium to prevent embryo implantation . The molecular targets include the progesterone receptor and, to a lesser extent, the glucocorticoid receptor .

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 .

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) primarily used as an emergency contraceptive. Its biological activity is characterized by its ability to modulate progesterone receptor activity, influencing reproductive processes such as ovulation and endometrial proliferation. This article delves into UPA's mechanisms, pharmacokinetics, clinical efficacy, and safety profile, supported by relevant data and case studies.

This compound acetate acts predominantly through its interaction with progesterone receptors. Depending on the tissue context and the presence of progesterone, it can exhibit both agonistic and antagonistic properties:

• Ovulation Inhibition : UPA primarily inhibits or delays ovulation by suppressing luteinizing hormone (LH) surges, thus postponing follicular rupture .
• Endometrial Effects : It reduces endometrial thickness, which is crucial for implantation, and has been shown to induce apoptosis in fibroid cells, leading to a decrease in fibroid size .
• Transport Interference : UPA may also interfere with the transport of oocytes or zygotes through the fallopian tubes .

Pharmacokinetics

This compound acetate exhibits specific pharmacokinetic properties that influence its clinical use:

• Absorption : Tmax (time to reach maximum concentration) is approximately 60-90 minutes post-administration with a Cmax of 176 ± 89 ng/mL .
• Half-Life : The elimination half-life is about 32 hours, allowing for sustained biological activity .
• Protein Binding : UPA binds extensively to plasma proteins (97-99%), affecting its bioavailability and distribution .

Table 2: Pharmacokinetic Parameters

Clinical Efficacy

This compound acetate has been shown to be effective in preventing pregnancy when taken after unprotected intercourse. A pooled analysis from Phase III studies indicated:

• Pregnancy Rates : The overall pregnancy rate among women using UPA was reported at 1.9% .
• Efficacy Over Time : Efficacy decreases with time after unprotected intercourse:
  • Within 24 hours: Higher efficacy
  • After 72 hours: Notable decrease in effectiveness
• Comparison with Levonorgestrel : UPA demonstrated a lower pregnancy rate compared to levonorgestrel across various time intervals post-intercourse .

Table 3: Efficacy Data from Clinical Trials

Safety Profile

This compound acetate is generally well tolerated. Common adverse effects include:

• Headache
• Nausea
• Fatigue
• Dizziness
• Abdominal pain

These effects are typically mild to moderate and resolve spontaneously . Notably, UPA may cause a delay in the onset of the next menstrual period, although this is usually transient.

Case Study Insights

In a study involving over 2,200 women seeking emergency contraception:

• Participants : Included women aged between 15 and 44 years.
• Results : Of those treated with UPA, pregnancy was prevented in approximately 62.3% of cases compared to expected rates without intervention .

Basic Research Questions

Q. What are the primary pharmacological mechanisms of Ulipristal acetate (UPA) in emergency contraception, and how do they differ from other selective progesterone receptor modulators (SPRMs)?

• Methodological Answer : Investigate UPA’s mechanism via in vitro progesterone receptor binding assays and transcriptional activity profiling. Compare its binding affinity and downstream effects (e.g., inhibition of ovulation, endometrial thickening) with mifepristone using cell-based models. Hormonal assays (e.g., LH, progesterone) in clinical trials can track ovulation suppression timing and efficacy .

Q. What experimental models are most suitable for evaluating UPA’s contraceptive efficacy, and what are their translational limitations?

• Methodological Answer : Rodent models (rats, mice) are standard for embryofetal toxicity studies, while non-human primates better approximate human ovarian cycles. Limitations include species-specific pharmacokinetics (e.g., drug metabolism) and ethical constraints. Use serial ultrasounds and hormonal monitoring in primate studies to validate ovulation inhibition timelines .

Q. How should pharmacokinetic (PK) studies of UPA be designed to account for variability in absorption and metabolism across populations?

• Methodological Answer : Conduct cross-over trials with controlled dosing (e.g., 30 mg single dose) in diverse cohorts (e.g., BMI, hepatic function). Use LC-MS/MS to measure plasma concentrations of UPA and its active metabolite, monodemethyl-UPA, over 120 hours. Compare AUC and half-life between subgroups to identify covariates .

Q. What are the ethical considerations when recruiting participants for UPA trials, particularly regarding lactation or pregnancy exposure?

• Methodological Answer : Exclude lactating individuals or design studies with rigorous informed consent, including infant monitoring for adverse effects. For inadvertent pregnancy exposure, follow longitudinal registries (e.g., EMA’s post-marketing surveillance) to track outcomes, adjusting for confounding factors like maternal age and comorbidities .

Q. How can researchers standardize data collection on UPA’s endometrial effects to improve cross-study comparability?

• Methodological Answer : Use transvaginal ultrasound for endometrial thickness measurements and histopathological grading (e.g., PIP biopsy scoring). Harmonize protocols across sites via centralized training and blinded analysis to reduce interobserver variability .

Advanced Research Questions

Q. How can contradictions in UPA’s ovulation suppression efficacy across fertility windows be resolved?

• Methodological Answer : Stratify clinical trial participants by follicular phase (early vs. late pre-ovulatory) using LH surge detection. Conduct meta-analyses of existing trials (e.g., Brache et al., 2013 vs. Li et al., 2016) to quantify efficacy heterogeneity. Apply mixed-effects models to adjust for cycle variability and dosing timing .

Q. What methodological approaches address the extrapolation of UPA’s embryofetal toxicity data from animals to humans?

• Methodological Answer : Compare dose-normalized exposure metrics (e.g., mg/m² or AUC) between species. Use in vitro human placental models to assess drug transfer and toxicity pathways (e.g., apoptosis markers). Validate findings with epidemiological data from unintended pregnancy registries .

Q. How can long-term studies on UPA’s impact on ovarian reserve be designed to minimize confounding by concurrent therapies?

• Methodological Answer : Conduct prospective cohort studies with AMH (Anti-Müllerian Hormone) and antral follicle count (AFC) as endpoints. Exclude participants using hormonal contraceptives or SPRMs within 6 months. Apply propensity score matching to control for age and baseline ovarian reserve .

Q. What statistical techniques are optimal for analyzing UPA’s non-contraceptive effects (e.g., fibroid reduction) in heterogeneous populations?

• Methodological Answer : Use subgroup analysis or machine learning (e.g., random forests) to identify predictors of therapeutic response (e.g., fibroid size, hormonal status). Address missing data via multiple imputation and sensitivity analyses .

Q. How can researchers reconcile discrepancies in UPA’s post-fertilization effects observed in animal vs. human studies?

• Methodological Answer : Design hybrid preclinical-clinical studies using human endometrial organoids and murine embryo co-cultures. Compare UPA’s effects on implantation markers (e.g., LIF, integrins) across models. Validate with transcriptomic profiling of clinical endometrial samples post-UPA exposure .