Aprepitant

Synthetic Routes and Reaction Conditions: Aprepitant is synthesized through a multi-step process involving several key intermediates. The synthesis typically starts with the preparation of a morpholine derivative, which is then subjected to various chemical reactions, including alkylation, acylation, and cyclization . The final product is obtained through purification and crystallization steps to ensure high purity and yield .

Industrial Production Methods: In industrial settings, the production of this compound involves optimizing the reaction conditions to maximize yield and minimize impurities. Techniques such as high-performance liquid chromatography (HPLC) and gas chromatography (GC) are used to monitor the reaction progress and ensure the quality of the final product . Additionally, advanced formulation techniques, such as nanoprecipitation and solid dispersion, are employed to enhance the solubility and bioavailability of this compound .

Types of Reactions: Aprepitant undergoes various chemical reactions, including oxidation, reduction, and substitution . These reactions are essential for modifying the chemical structure and improving the pharmacological properties of the compound.

Common Reagents and Conditions: Common reagents used in the synthesis of this compound include alkylating agents, acylating agents, and reducing agents . The reactions are typically carried out under controlled conditions, such as specific temperatures, pressures, and pH levels, to ensure optimal yields and minimal side reactions .

Major Products Formed: The major products formed from the chemical reactions of this compound include its various intermediates and the final active pharmaceutical ingredient (API) . These products are characterized using techniques such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared (IR) spectroscopy to confirm their structures and purities .

Chemotherapy-Induced Nausea and Vomiting (CINV)

Overview
Aprepitant is predominantly used in combination with other antiemetic agents to manage CINV, especially in patients receiving highly emetogenic chemotherapy. The drug's efficacy has been established through multiple clinical trials.

Efficacy Data
A systematic review highlighted the effectiveness of this compound in preventing CINV. In a phase III study, patients receiving this compound demonstrated a complete response rate of 83.2% compared to 71.3% in the control group (P < 0.05) .

Antitumor Effects

Mechanism of Action
Recent studies have indicated that this compound may possess antitumor properties. Research has shown that it induces apoptosis in tumor cells and can reduce tumor volume in animal models .

Case Studies
In preclinical trials involving human osteosarcoma and hepatoblastoma xenografts, this compound significantly decreased tumor size when administered alongside conventional therapies .

Dermatological Applications

Topical Use
this compound has been explored for its topical application to mitigate side effects associated with other cancer treatments, such as erlotinib-induced dermatitis and hair loss. In a study involving rats, topical administration of this compound resulted in up to a 70% reduction in neutrophil activity related to inflammation caused by erlotinib .

Potential Use in Other Conditions

Pruritus Management
Emerging research suggests that this compound may be effective in treating pruritus (itching) associated with various conditions, particularly in cancer patients .

Antiviral Properties
Studies have also hinted at the antiviral effects of this compound, suggesting its potential use against certain viral infections by modulating immune responses .

Aprepitant exerts its effects by selectively blocking the neurokinin-1 (NK1) receptors in the brain . These receptors are activated by substance P, a neuropeptide involved in the vomiting reflex . By inhibiting the binding of substance P to NK1 receptors, this compound effectively prevents the transmission of signals that trigger nausea and vomiting . This mechanism of action makes this compound a valuable adjunct therapy in combination with other antiemetic agents, such as serotonin (5-HT3) receptor antagonists and corticosteroids .

Aprepitant is often compared with other antiemetic agents, such as ondansetron and dexamethasone . While ondansetron is a serotonin (5-HT3) receptor antagonist and dexamethasone is a corticosteroid, this compound is unique in its mechanism of action as an NK1 receptor antagonist . This distinct mechanism allows this compound to complement traditional antiemetic drugs and enhance the control of chemotherapy-induced nausea and vomiting . Other similar compounds include fosthis compound, a prodrug of this compound, which is converted to this compound in the body and shares the same mechanism of action .

Aprepitant is a neurokinin-1 (NK-1) receptor antagonist primarily used for the prevention of chemotherapy-induced nausea and vomiting (CINV). Recent research has expanded its potential applications, particularly in oncology, where it has shown promise as an anticancer agent. This article delves into the biological activity of this compound, highlighting its mechanisms of action, efficacy in clinical studies, and emerging roles in cancer therapy.

This compound functions by selectively blocking the NK-1 receptors in the central nervous system, which are activated by substance P, a neuropeptide involved in the vomiting reflex. By inhibiting these receptors, this compound effectively reduces both acute and delayed phases of CINV induced by chemotherapeutic agents such as cisplatin .

Recent studies have revealed additional mechanisms through which this compound exerts its effects:

• Induction of Immunogenic Cell Death : this compound has been shown to activate the anticipatory unfolded protein response (a-UPR), leading to necrotic cell death that stimulates immune responses. This process involves the release of damage-associated molecular patterns (DAMPs), such as HMGB1 and ATP, which enhance macrophage migration and activation .
• Calcium Release and Stress Response Activation : The drug appears to trigger calcium release from the endoplasmic reticulum, resulting in hyperactivation of stress response pathways that contribute to its anticancer effects .

Chemotherapy-Induced Nausea and Vomiting (CINV)

A meta-analysis encompassing 23 randomized controlled trials with 7,956 patients demonstrated that this compound-containing regimens significantly improved complete response rates for CINV compared to standard therapies. The results indicated:

• Complete Response Rates : 50.3% in standard therapy vs. 66.4% and 70.5% in this compound 40/25 mg and 125/80 mg groups respectively .
• Safety Profile : No significant differences in severe adverse events were noted between groups; however, higher incidences of fatigue and hiccups were observed in the this compound group .

Case Studies

A case study reported successful outcomes using this compound for refractory postoperative nausea and vomiting, suggesting its utility beyond traditional applications .

Efficacy Against Cancer Cells

Recent preclinical studies have established that this compound not only alleviates nausea but also induces cell death in various cancer types:

• Breast Cancer Models : this compound treatment resulted in typical features of necrotic cell death, including cell swelling and membrane rupture. This mode of action was confirmed through both 2D cell culture and 3D organoid models .

Summary of Key Trials

Q. Basic: How are randomized controlled trials (RCTs) designed to evaluate aprepitant's efficacy in chemotherapy-induced nausea and vomiting (CINV)?

RCTs for this compound typically employ a double-blind, placebo-controlled design with standardized antiemetic regimens. Key endpoints include "complete response" (no emesis/no rescue therapy) over 5 days post-chemotherapy. For example, in cisplatin-based chemotherapy, this compound (125 mg orally on day 1; 80 mg on days 2–3) is combined with ondansetron and dexamethasone, while the control group receives standard dual therapy . Statistical analysis uses logistic regression models to compare outcomes, with significance thresholds at p < 0.05. Sample sizes are calculated to ensure power (e.g., 260 patients per group in Study 052) .

Q. Basic: What preclinical models validate this compound's pharmacokinetics and brain penetration?

Ferrets are a validated preclinical model due to human-like NK1 receptor pharmacology. Studies administer this compound orally (1–3 mg/kg) and measure plasma and brain concentrations via LC-MS. For instance, brain cortex levels reach 80–150 ng/g 24 hours post-dose, correlating with sustained antiemetic efficacy against cisplatin-induced emesis . Plasma clearance (~1.5 mL/min/kg) and metabolite profiling (parent compound dominance) confirm this compound’s stability and primary role in efficacy .

Q. Advanced: How can conflicting pharmacokinetic data in patient subpopulations be resolved?

Conflicting data, such as age-related effects on this compound clearance in Japanese patients, require meta-analysis and covariate adjustment. For example, one study found no correlation between age and plasma exposure (n = 44), while another (n = 315) reported mild age-dependent clearance changes . Methodological solutions include:

• Stratified randomization in trials.
• Population pharmacokinetic modeling to quantify covariates (e.g., CYP3A4 activity).
• Sensitivity analyses excluding outliers .

Q. Advanced: What methodologies elucidate this compound's off-target mechanisms, such as nSMase2 inhibition?

Virtual screening (e.g., molecular docking) identifies this compound’s interaction with nSMase2, validated via:

• Cell-free assays : Measure enzyme activity inhibition (IC50 values).
• Cell-dependent assays : Quantify exosome suppression in HCT116 cells (e.g., 15 µM this compound reduces exosome release without cytotoxicity) .
• Structural dynamics : RMSD plots confirm stable this compound–nSMase2 binding . Complementary techniques like Western blotting assess downstream biomarkers (e.g., ceramide levels).

Q. Basic: How are drug-drug interaction (DDI) risks assessed for this compound?

DDI studies focus on CYP3A4-mediated metabolism:

• In vitro assays : Human liver microsomes quantify this compound’s inhibition/induction potential.
• Clinical PK studies : Co-administration with CYP3A4 substrates (e.g., dexamethasone) or inhibitors (e.g., ketoconazole) to measure AUC changes .
• Population PK models : Adjust dosing for patients on concurrent CYP3A4 modulators .

Q. Advanced: How is this compound repurposed for exosome inhibition in cancer therapy?

Repurposing strategies involve:

• Dose-response assays : Test this compound (1–50 µM) in cell lines (e.g., HCT116) to determine IC50 for nSMase2.
• Functional validation : Measure exosome markers (CD63, Alix) via ELISA or nanoparticle tracking analysis .
• In vivo models : Xenograft studies assessing tumor exosome suppression and metastasis .

Q. Basic: How is statistical power determined in this compound trials?

Sample size calculations use the formula:
$n = \frac{(Z_{\alpha/2} + Z_\beta)^2 \cdot p(1-p)}{(p_1 - p_0)^2}$

where p = pooled proportion, α = 0.05, and power (1–β) = 80%. For example, a study with 200 patients per group achieved 95% confidence to detect a 20% efficacy difference .

Q. Advanced: What mechanistic studies validate this compound's anti-inflammatory effects via NF-κB?

In LPS-induced macrophages:

• ROS measurement : Fluorescent probes (e.g., DCFH-DA) quantify oxidative stress suppression.
• Cytokine profiling : ELISA for TNF-α, IL-6, and MCP-1.
• Western blotting : Assess NF-κB pathway proteins (e.g., p65 phosphorylation, IκBα degradation) .

Q. Basic: How are animal models standardized for this compound reproducibility?

• Species selection : Ferrets for emesis studies (NK1 receptor homology); rodents for PK/PD.
• Dosing consistency : Fixed mg/kg ratios (e.g., 3 mg/kg in ferrets).
• Endpoint alignment : Emesis frequency, brain/plasma ratios, and receptor occupancy (autoradiography in gerbils) .

Q. Advanced: How are structure-activity relationship (SAR) studies conducted for this compound analogues?

• Molecular docking : Compare SF5- vs. CF3-substituted analogues binding to NK1R (e.g., Glide/SP scoring).
• Quantum chemical calculations : Fragment Molecular Orbital (FMO) analysis to predict affinity .
• In vitro binding assays : Radioligand displacement (e.g., [³H]-substance P) .