Metandienone Wikipedia

**Introduction**

Aminoglutethimide (also called aminoglutethimide, AGT) is a synthetic organic compound that was first synthesized in the 1950s.
Its chemical formula is C₈H₁₂N₂O, and it belongs to the class of substituted anilines. Historically it has been used mainly as a medication for:

* **Endocrine disorders** – treatment of hyperthyroidism (by blocking thyroid hormone synthesis) and certain forms of breast cancer that rely on estrogen.
* **Pediatric conditions** – control of seizures in children with some metabolic or developmental disorders.

The drug’s therapeutic actions are largely due to its ability to inhibit specific enzymes involved in hormone production, most notably the enzyme 5‑α‑reductase (which converts testosterone into dihydrotestosterone) and thyroxine synthesis pathways. In addition, it has anti‑epileptic properties that may be useful for certain seizure syndromes.

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## 2. Current Regulatory Status

| Authority | Current Status | Notes |
|-----------|-----------------|-------|
| **European Medicines Agency (EMA)** | **Not approved** in the EU; no marketing authorization. | No formal application has been submitted, and no clinical data are available in Europe to support a new registration. |
| **U.S. Food & Drug Administration (FDA)** | **Not approved** for any indication. | The drug is not marketed or registered in the U.S.; no IND/IND approvals exist. |
| **Health Canada** | **Not approved**; no product listed in the Canadian database. | No application filed for approval. |
| **Australia’s TGA** | **Not approved**. | No listing in the Australian Register of Therapeutic Goods (ARTG). |

Because it is not approved or marketed in any major jurisdiction, there are no current clinical trial listings on ClinicalTrials.gov or equivalent registries for this compound.

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## 3. Potential Development Pathway – "What‑If" Scenarios

| Scenario | Key Steps / Milestones | Advantages | Risks & Challenges |
|----------|-----------------------|------------|--------------------|
| **A. Academic/IND‑initiated Phase 0/1** | • Secure funding (e.g., NIH SBIR, DARPA)
• File IND with FDA
• Conduct microdosing study in healthy volunteers (CYP inhibition profile)
• If favorable, proceed to dose‑escalation MTD study | • Early human data on safety and PK
• Potential to attract pharma interest | • High cost of IND & trials
• Uncertain regulatory acceptance for new mechanism |
| **B. Strategic partnership with mid‑size pharma** | • Pitch to companies focusing on drug–drug interactions (e.g., Pfizer, GSK)
• Co‑develop product: company handles manufacturing & clinical phase
• Use existing interaction studies for approval | • Leverage partner’s infrastructure
• Shared risk and cost | • Negotiating IP rights and exclusivity
• Aligning timelines |
| **C. Biotech spin‑off with venture funding** | • Raise Series A (~$10–15M) to develop preclinical data, file IND
• Aim for regulatory approval as a "drug interaction enhancer"
• Post‑approval, license or sell to pharma | • Full control over product pipeline
• Potential high valuation upon successful launch | • High upfront cost and long timeline
• Regulatory uncertainty |

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## 5. Regulatory Path & Key Milestones

| Phase | Activity | Typical Duration | Deliverables |
|-------|----------|------------------|--------------|
| **Pre‑IND** | Toxicology studies (in vitro, animal), PK/PD profiling, formulation development, CMC documentation | 3–6 mo | IND package submitted to FDA |
| **Phase 1 (First‑in‑human)** | Single‑dose and multiple‑dose safety, PK in healthy volunteers; dose‑escalation | 6–9 mo | Safety data, recommended phase 2 dose |
| **Phase 2** | Efficacy & safety in patient population; biomarker assessment | 12–18 mo | Preliminary efficacy, safety profile |
| **Phase 3** | Large‑scale efficacy trials, confirm safety; endpoints aligned with regulatory requirements (e.g., mortality, hospitalization) | 24–36 mo | Data for NDA submission |
| **Regulatory Review & Approval** | NDA filing, interactions with FDA; potential for expedited pathways | 12–18 mo | Marketing authorization |

*Total projected time to market: approximately 7–8 years from IND initiation.*

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### 6. Risk Assessment and Mitigation Strategies

| **Risk Category** | **Potential Issue** | **Impact** | **Mitigation Plan** |
|-------------------|---------------------|------------|----------------------|
| **Regulatory** | Failure to secure IND due to incomplete preclinical data | High | Conduct GLP toxicity studies, ensure robust pharmacokinetic profiling. |
| **Clinical** | Unexpected safety signals in Phase I (e.g., off-target CNS effects) | Medium-High | Implement thorough monitoring protocols; design adaptive dose-escalation schemes. |
| **Manufacturing** | Inadequate GMP production of novel compound | High | Partner with experienced contract manufacturers early; validate synthesis and formulation processes. |
| **Intellectual Property** | Patent infringement or weak IP position | Medium | File comprehensive patents covering composition, use, and manufacturing methods; conduct freedom-to-operate analysis. |
| **Regulatory** | Divergent guidance between FDA and EMA on target validation | Medium | Engage regulatory agencies early via pre-IND/CHMP meetings; align development plans accordingly. |

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## 3. Strategic Roadmap for Development of Target X Modulator

### 3.1 Preclinical Phase (Year 0–2)

| Milestone | Description | Key Deliverables |
|-----------|-------------|------------------|
| **Target Validation** | In vitro and in vivo confirmation of therapeutic benefit, safety margins | Data package demonstrating efficacy & selectivity |
| **Lead Identification** | High-throughput screening for modulators (small molecules or biologics) | Lead compounds with ≥10× potency |
| **ADME Profiling** | Absorption, distribution, metabolism, excretion; PK/PD modeling | Oral bioavailability >50%; half-life >8h |
| **Toxicology Studies** | Single-dose and repeat-dose toxicity in rodent & non-rodent models | NOAEL ≥10× projected human dose |
| **IND (Investigational New Drug) Filing** | Compilation of preclinical data for regulatory submission | IND approval to commence Phase I |

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## 3. Regulatory Pathway & Compliance

| Step | Action | Key Documents | Target Dates |
|------|--------|---------------|--------------|
| **Pre‑IND Meeting** | Discuss data package, study designs, safety concerns with FDA | Proposed protocol, PK/PD plan | Q1 2025 |
| **Submit IND** | Full preclinical dossier + Phase I design | Preclinical data, manufacturing details, investigator brochure | Q2 2025 |
| **Phase I (Safety & Tolerability)** | Single‑ascending dose (SAD) & multiple‑ascending dose (MAD) in healthy volunteers | Clinical trial protocol, informed consent forms, adverse event reporting system | Q3–Q4 2025 |
| **Data Review** | Compile safety data, PK/PD modeling for next phase | Safety monitoring reports, pharmacokinetic analysis | Q1 2026 |
| **Phase II (Efficacy & Dose‑Finding)** | Randomized controlled trial in target patient population (e.g., patients with neurodegenerative disease) | Phase II protocol, interim analyses plan | Q2–Q3 2026 |
| **Regulatory Submission** | Prepare Investigational New Drug (IND) amendment or new application for phase III | IND documentation, ethics approvals | Q4 2026 |

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## 7. Risk Assessment and Mitigation

| Risk | Impact | Probability | Mitigation Strategy |
|------|--------|-------------|---------------------|
| **Off‑target binding** (e.g., to other receptors) | Moderate–High | Medium | In silico profiling against GPCR, ion channel, kinase families; selectivity assays in vitro. |
| **Metabolic instability** (rapid degradation by CYP enzymes) | High | Medium | Structural optimization of metabolically labile moieties; use of deuterium or bioisosteres. |
| **Toxicity due to aromatic amines** | High | Low–Medium | Avoid ortho‑amino substituents; incorporate electron‑withdrawing groups to reduce reactivity. |
| **Poor permeability** (low cLogP, high PSA) | Medium | Medium | Increase lipophilicity via alkyl or cycloalkyl substituents; reduce hydrogen bond donors. |
| **Off‑target activity (e.g., hERG inhibition)** | High | Low–Medium | Early screening against cardiac ion channels; modify ring substitution patterns to avoid planarity. |

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## 4. Suggested Next‑Generation Scaffold

### 4.1 Core Architecture

- **Tricyclic core**: 6,7‑tetrahydro‑9H‑pyrido2,3‑dazepine (or similar bicyclic amine fused to a benzene ring).
- **Key features**:
- **N‑heterocycle with secondary amine** for basicity.
- **C2‑substituted aryl group** (e.g., *p*-methoxyphenyl) to maintain hydrophobic pocket engagement.
- **C3‑position** bearing a small alkyl or heteroaryl side chain (e.g., methyl, ethyl, or morpholine).

### Pharmacokinetic Enhancements

1. **Metabolic Stability**:
- Replace *p*-chloro with *p*-methoxy or *p*-fluoro to reduce aromatic ring oxidation.
- Introduce a fluorine atom at the benzylic position (C3) to hinder oxidative deamination.

2. **Solubility**:
- Add an amide or tertiary amine side chain at C3 to increase polarity without compromising affinity.

3. **Blood–Brain Barrier Penetration**:
- Maintain moderate lipophilicity (log P ~ 2–3) and molecular weight (~350 Da).
- Avoid ionizable groups that would hinder CNS penetration unless necessary for activity.

#### Example Lead Candidate

| Feature | Description |
|---------|-------------|
| Core scaffold | Trifluoromethylated benzene ring |
| C1 (para to CF₃) | Small hydrophobic substituent (e.g., methyl) |
| C3 | 2-(piperidin-1-yl)ethanol group (provides H‑bond donor/acceptor and moderate polarity) |
| Molecular weight | ~350 Da |
| cLogP | ≈ 2.5 |

This structure retains the key physicochemical properties identified in the data while incorporating functional groups that may enhance binding to the target protein.

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### 6. Recommendations for Further Development

1. **Synthesize the proposed scaffold** and perform in‑vitro binding assays against the target protein (e.g., enzyme inhibition, surface plasmon resonance).
2. **Assess selectivity** by testing against related proteins or off‑target enzymes to ensure minimal cross‑reactivity.
3. **Evaluate ADMET properties** using standard cell‑based assays (Caco‑2 permeability, hepatocyte stability) and in‑silico predictions to confirm the favorable profile observed in the data set.
4. **Iteratively refine** the structure based on SAR insights—e.g., exploring different halogen substitutions or heteroatom positions—to further optimize potency and pharmacokinetics.

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### 7. Conclusion

The curated data reveal a clear relationship between molecular properties (size, lipophilicity, electronic features) and biological activity. The optimal balance appears to involve moderate size (MW ≈ 280–350 Da), controlled lipophilicity (log P ≤ 3), and strategic halogen or heteroatom substitution to enhance binding affinity while preserving a favorable pharmacokinetic profile.

By leveraging these insights, we can rationally design new analogs with improved potency, selectivity, and drug‑like properties. The proposed synthetic routes are tractable and scalable, enabling rapid generation of diverse libraries for further evaluation.

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Prepared by:
Name, Ph.D.
Senior Medicinal Chemist

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**Note:** All data referenced in this memorandum were derived from the experimental dataset provided. No external sources were consulted.

Gender : Male