Bicalutamide

Synthetic Routes and Reaction Conditions: The synthesis of Bicalutamide involves several key stepsThis oxidation is typically carried out using potassium permanganate in the presence of water or a mixture of water and a water-miscible solvent . The resulting product is this compound.

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process is designed to be simple, convenient, safe, and cost-effective. The key steps involve the preparation of the sulfide compound, followed by its oxidation to form this compound .

Types of Reactions: Bicalutamide undergoes several types of chemical reactions, including:

Oxidation: The primary reaction in the synthesis of this compound involves the oxidation of the sulfide compound to form the sulfone compound.

Substitution: this compound can undergo substitution reactions, particularly involving the cyano and trifluoromethyl groups on the phenyl ring.

Common Reagents and Conditions:

Oxidizing Agents: Potassium permanganate, peroxy acids such as m-chloroperbenzoic acid.

Solvents: Water, methanol, methylene chloride.

Major Products Formed: The major product formed from the oxidation reaction is this compound itself, which is a sulfone compound .

Prostate Cancer Treatment

• Early and Advanced Prostate Cancer : Bicalutamide is approved for the treatment of stage D2 metastatic prostate cancer when used alongside surgical or medical castration. It is also administered as monotherapy for stage C or D1 locally advanced prostate cancer at a dosage of 150 mg/day .
• Survival Benefits : A study indicated that patients receiving this compound had a 76.3% overall survival rate at 12 years compared to 71.3% in the placebo group, highlighting its effectiveness in prolonging survival .

Hormonal Therapy

• Transgender Care : this compound is used in hormone therapy for transgender women to block testosterone effects and manage symptoms associated with high testosterone levels in women .
• Puberty Blocker : It is also employed to prevent premature puberty in transgender girls and treat early puberty in boys .

Other Indications

• This compound has shown potential in treating skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women .
• Research suggests its utility in managing paraphilias and hypersexuality in men .

Efficacy

• This compound has demonstrated comparable efficacy to castration therapies while preserving sexual interest better than traditional methods .
• Studies have shown that it can effectively inhibit androgen-mediated cell adhesion in prostate cancer cells, potentially reducing metastasis risk .

Side Effects

• Common side effects include breast pain and gynecomastia, which are typical for antiandrogens. However, this compound has a more favorable tolerability profile compared to other antiandrogens like flutamide .
• Long-term follow-up studies have indicated that while side effects exist, they are generally manageable and do not outweigh the benefits of treatment .

Case Studies

Bicalutamide works by competitively inhibiting the binding of androgens such as dihydrotestosterone and testosterone to androgen receptors. This inhibition prevents the stimulation of cell growth in prostate cancer . This compound binds to the androgen receptor without activating gene expression, leading to the regression of prostatic tumors . The molecular targets involved include the androgen receptors in prostate cancer cells .

Structural and Functional Comparisons

Bicalutamide belongs to the diarylpropionamide class of antiandrogens, characterized by a sulfonyl linkage between two aromatic rings. This structure contrasts with:

• Flutamide : A nitroaromatic compound metabolized into hydroxyflutamide, its active form. Unlike this compound, flutamide undergoes rapid hepatic oxidation and has a shorter half-life (~5–6 hours) .
• Enzalutamide : A second-generation antiandrogen with a bulky hydrophobic side chain, enabling stronger AR binding and inhibition of nuclear translocation .
• Novel analogs: Derivatives like deshydroxy (compound 16) and acetylated (compound 27) this compound analogs demonstrate enhanced AR antagonism through modifications to the sulfonyl group or hydroxyl substitution .

In Vitro and Preclinical Data

Table 1: In Vitro Antiproliferative Activity (IC₅₀, µM) in Prostate Cancer Cell Lines

Data derived from in vitro studies comparing this compound, enzalutamide, and novel analogs .

Key findings:

• The deshydroxy analog (16 ) exhibited 6–8× greater potency than this compound across all cell lines .
• Sulfone derivatives (e.g., compound 21 ) showed reduced activity compared to sulfide analogs, attributed to unfavorable hydrogen bonding in AR’s ligand-binding domain (LBD) .
• Smaller chemical scaffolds (e.g., phenylsulfonyl-benzamides) demonstrated AR antagonism comparable to this compound, suggesting structural flexibility in drug design .

Table 2: Clinical Outcomes and Adverse Effects

Key comparisons:

• Efficacy: Enzalutamide showed superior PSA reduction and survival in metastatic castration-resistant prostate cancer (mCRPC), while this compound demonstrated non-inferiority to castration in localized disease .
• Quality of Life (QoL) : this compound preserved sexual interest and erectile function better than luteinizing hormone-releasing hormone (LHRH) analogs, with 25% vs. 53% grade ≥2 erectile dysfunction at 2 years .
• Safety: this compound monotherapy had fewer visual disorders and hot flushes than nilutamide-based combined androgen blockade (CAB) but higher rates of gynecomastia .

Pharmacokinetic and Metabolic Profiles

• Flutamide : Rapidly oxidized to hydroxyflutamide, with a half-life of 5–6 hours and higher hepatotoxicity risk .

Bicalutamide is a nonsteroidal antiandrogen primarily used in the treatment of prostate cancer. Its biological activity is characterized by its ability to inhibit androgen receptors, thereby blocking the action of androgens like testosterone. This article provides a comprehensive overview of the biological activity of this compound, including its pharmacokinetics, mechanisms of action, clinical efficacy, and adverse effects.

Pharmacokinetics

This compound is administered orally, with a recommended dosage of 150 mg once daily for early nonmetastatic prostate cancer and 50 mg daily in combination with luteinizing hormone-releasing hormone analogues for advanced cases. Its pharmacokinetic profile reveals:

• Absorption : The (R)-enantiomer is absorbed slowly and saturably, while the (S)-enantiomer is more rapidly absorbed and cleared. Food intake does not significantly affect absorption.
• Elimination Half-life : Approximately one week, leading to a tenfold accumulation in plasma during daily administration.
• Metabolism : Primarily metabolized by cytochrome P450 enzymes, particularly CYP3A4. The (R)-enantiomer has potential inhibitory effects on CYP3A4 but does not show clinically relevant inhibition in vivo at standard doses .

This compound functions as a competitive antagonist at androgen receptors in target tissues such as the prostate. By binding to these receptors, it prevents androgens from exerting their biological effects, which is critical in managing androgen-dependent cancers.

Prostate Cancer Treatment

This compound has been extensively studied for its efficacy in treating prostate cancer. A notable study compared this compound monotherapy (50 mg/day) to castration. Results indicated that while this compound was associated with fewer adverse effects, it was inferior to castration regarding overall response rates and survival metrics:

• Time-to-Treatment Failure : Hazard ratio of 1.59 favoring castration.
• Prostate-Specific Antigen (PSA) Reduction : this compound showed a median fall of 86-88%, compared to 96-97% for castration .

Case Studies

• Phase II Trial in Breast Cancer : A multicenter trial assessed this compound's effectiveness in women with androgen receptor-positive metastatic breast cancer. The primary endpoint was the clinical benefit rate, which included complete responses and stable disease over six months. The results indicated potential benefits in this patient population, warranting further investigation .
• Weekly Administration Trial : A phase I-II trial evaluated the safety and activity of weekly this compound administration in men with elevated PSA levels. Results showed a significant reduction in PSA levels (50% reduction noted) and an improvement trend in high-grade prostatic intraepithelial neoplasia (HG-PIN) status among treated subjects .

Adverse Effects

While this compound is generally well-tolerated, it can lead to various side effects:

• Common Adverse Effects : Breast tenderness, gynecomastia, hot flushes, and liver enzyme alterations.
• Quality of Life Impact : Although some patients reported improved sexual functioning initially compared to those receiving castration, long-term studies indicate that higher doses may be needed to achieve comparable efficacy .

Comparative Efficacy Table

Basic Research Questions

Q. What experimental models are commonly used to investigate bicalutamide’s efficacy in androgen receptor (AR)-related pathologies, and how should researchers optimize dosing regimens?

• Methodological Guidance : Preclinical studies often employ knock-in (KI) mouse models, such as the AR113Q spinal and bulbar muscular atrophy (SBMA) model, to mimic human disease progression. This compound is administered subcutaneously (2 mg/kg twice weekly) in oil-based vehicles, with outcomes assessed via survival analysis (Kaplan-Meier curves) and motor behavior tests (rotarod, grip strength) . LC-MS is recommended for validating serum and tissue drug levels to ensure pharmacokinetic consistency .

Q. How can researchers design clinical trials to evaluate this compound’s impact on prostate cancer progression while minimizing bias?

• Methodological Guidance : Use the PICOT framework to structure trials:

• P opulation: Patients with locally advanced or metastatic prostate cancer (e.g., T1b-T4, M0).
• I ntervention: this compound 150 mg/day + standard care (radical prostatectomy, radiotherapy).
• C omparison: Placebo + standard care.
• O utcome: Progression-free survival (PFS), overall survival (OS).
• T ime: Median 5.4-year follow-up.
  Stratify subgroups (e.g., localized vs. locally advanced disease) to address outcome discrepancies, as this compound benefits locally advanced patients but may harm those with localized disease .

Q. What analytical methods ensure reliable quantification of this compound in pharmaceutical formulations and biological samples?

• Methodological Guidance :

• Pharmaceutical purity : Use reverse-phase HPLC with UV detection (λ = 270 nm), validated per ICH guidelines. Ensure mobile phases include diluted phosphoric acid and acetonitrile for optimal resolution of related substances (e.g., isomers, degradation products) .
• Biological samples : LC-MS/MS for serum and tissue quantification, with calibration curves adjusted for matrix effects .

Advanced Research Questions

Q. How do AR variants (e.g., AR-V7) influence resistance to this compound, and what combinatorial strategies can overcome this?

• Methodological Guidance :

• Mechanistic studies : Use this compound-resistant cell lines (e.g., prostate cancer models) to quantify AR-V7 expression via qPCR/Western blot.
• Combinatorial therapy : Co-administer niclosamide (AR-V7 inhibitor) with this compound. Validate synergy using proliferation assays (Ki67 staining) and apoptosis markers (PARP cleavage) .
• Statistical analysis : Compare hazard ratios (HRs) for PFS between monotherapy and combination arms using Cox regression .

Q. What molecular pathways underlie this compound’s neuroprotective effects in SBMA, and how can autophagy modulation enhance therapeutic outcomes?

• Methodological Guidance :

• Autophagy analysis : Measure autophagic flux via LC3-II/p62 Western blot in skeletal muscle. This compound restores basal HSPB8 levels, resolving ARpolyQ aggregation. Combine with trehalose (autophagy inducer) to amplify efficacy .
• Mitochondrial markers : Quantify mtDNA copy number and OXPHOS enzyme accumulation to assess metabolic recovery .

Q. How should researchers resolve contradictions in survival outcomes from large-scale clinical trials (e.g., Early Prostate Cancer Program)?

• Methodological Guidance :

• Subgroup analysis : Stratify data by disease stage (localized vs. locally advanced). Use two-way ANOVA with Tukey’s post-hoc test to identify treatment effects within subgroups .
• Bias mitigation : Adjust for confounding variables (e.g., baseline PSA, Gleason score) using multivariate regression. Report HRs with 95% confidence intervals .

Q. What biomarkers predict this compound’s clinical benefit in AR-negative breast cancer, and how can they be validated?

• Methodological Guidance :

• Retrospective biomarker screening : Analyze archived tumor samples for AR splice variants or immune checkpoint markers (e.g., PD-L1) via immunohistochemistry.
• Validation cohort : Use a prospective trial design with pre-specified endpoints (e.g., 6-month clinical benefit rate). Apply log-rank tests to compare PFS between biomarker-positive and -negative cohorts .

Q. Methodological Best Practices

• Experimental Design :

  • For preclinical studies, use KI mouse models with endogenous AR expression to recapitulate human disease .
  • In clinical trials, prioritize stratified randomization to balance prognostic factors (e.g., tumor volume, Gleason score) .

• Data Analysis :

  • Employ two-way ANOVA with time and treatment as factors for longitudinal behavioral data .
  • Use Mantel-Cox tests for survival analysis and report median follow-up durations to contextualize maturity of data .

• Analytical Validation :

  • Include system suitability tests (e.g., column efficiency, peak symmetry) in HPLC protocols to ensure reproducibility .