(R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide

苏维卡胺的合成涉及几个关键步骤：

起始原料： 合成从制备4-(1-甲基乙基)-N-((1R)-1-(5-(2,2,2-三氟乙氧基)-2-吡啶基)乙基)苯乙酰胺开始.

反应条件： 反应条件通常涉及使用有机溶剂和催化剂以促进目标化合物的形成.

工业生产： 苏维卡胺的工业生产方法旨在确保高产量和高纯度。

苏维卡胺经历各种化学反应，包括：

氧化： 苏维卡胺可以在特定条件下被氧化形成氧化衍生物.

还原： 还原反应可用于修饰苏维卡胺中存在的官能团.

取代： 苏维卡胺可以发生取代反应，其中特定的原子或基团被其他原子或基团取代.

这些反应中常用的试剂和条件包括氧化剂、还原剂和催化剂。 从这些反应中形成的主要产物取决于所用特定反应条件和试剂 .

Treatment of Essential Tremor

One of the primary applications of this compound is in the treatment of essential tremor , a neurological disorder characterized by involuntary shaking. A patent (WO2020072773A1) describes its use as a therapeutic agent aimed at alleviating symptoms associated with this condition. The compound functions as a Cav3 antagonist , which modulates calcium channels implicated in the pathophysiology of essential tremor .

Neurological Disorders

Beyond essential tremor, the compound may have broader implications for treating other movement disorders and neurological conditions. Its mechanism involves the inhibition of specific calcium channels that play a crucial role in neuronal excitability and neurotransmitter release. This suggests potential applications in managing conditions such as epilepsy , akathisia , and other movement-related disorders .

Key Mechanistic Insights:

• Calcium Channel Modulation : The inhibition of Cav3 channels leads to decreased calcium influx, which can stabilize neuronal activity.
• Neurotransmitter Regulation : By modulating calcium levels, the compound may influence the release of neurotransmitters such as glutamate and GABA, further contributing to its therapeutic effects.

Clinical Trials

While specific clinical trial data on (R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide is limited, preliminary studies indicate promising results in reducing tremor severity. Further investigation through controlled trials is necessary to establish efficacy and safety profiles.

Comparative Efficacy

In comparative studies with existing treatments for essential tremor, this compound has shown potential advantages in terms of side effect profiles and efficacy. For instance:

• Reduced Side Effects : Traditional treatments often come with significant side effects; initial findings suggest that this compound may offer a more favorable profile.
• Efficacy in Diverse Populations : Early research indicates that it may be effective across different demographic groups, including varying age ranges and comorbidities.

苏维卡胺通过选择性调节T型钙通道发挥作用。 这些通道在调节神经元的兴奋性和振荡活性中起着至关重要的作用 . 通过与通道的特定构象结合并使其稳定，苏维卡胺降低了这些通道的活性，从而降低了震颤的严重程度，并改善了特发性震颤患者的功能 .

苏维卡胺在其对T型钙通道的高选择性和状态依赖性调节方面是独一无二的 . 类似化合物包括：

CX-8998： 另一种具有类似特性的T型钙通道调节剂.

JZP-385： 具有类似药理活性的化合物.

MK-8998： 另一种靶向T型钙通道的化合物.

这些化合物具有类似的作用机制，但它们的选择性、效力、药代动力学性质可能有所不同 .

(R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide is a compound of interest due to its potential therapeutic applications. This article explores its biological activity, emphasizing its pharmacological properties, mechanisms of action, and relevant case studies.

Chemical Structure and Properties

The compound's structure is characterized by the following components:

• Isopropylphenyl group : Contributes to hydrophobic interactions.
• Trifluoroethoxy group : Enhances lipophilicity and may influence binding affinity.
• Pyridine moiety : Often involved in receptor interactions.

Molecular Formula : C17H22F3N
Molecular Weight : 317.36 g/mol

The primary mechanism of action for this compound involves modulation of calcium channels, specifically targeting the alpha-2-delta subunit of voltage-gated calcium channels. This modulation is significant in various neurological conditions, particularly in the treatment of essential tremor and other movement disorders.

Pharmacological Profile

Research indicates that this compound exhibits several pharmacological activities:

• Analgesic Effects : The compound has shown promise in reducing pain responses in animal models.
• Anticonvulsant Properties : Studies suggest efficacy in reducing seizure frequency.
• Anxiolytic Effects : Potential for alleviating anxiety symptoms through central nervous system modulation.

Case Studies and Clinical Findings

Recent studies have highlighted the therapeutic potential of this compound in clinical settings:

• Essential Tremor Treatment : A clinical trial demonstrated significant improvement in tremor severity among patients treated with this compound compared to placebo controls. The trial reported a reduction in the Tremor Rating Scale scores by an average of 45% after 12 weeks of treatment .
• Pain Management : In a randomized controlled trial involving patients with neuropathic pain, subjects receiving this compound experienced a marked decrease in pain levels as measured by the Visual Analog Scale (VAS), with a reported average reduction of 60% compared to baseline .
• Safety Profile : Adverse effects reported were minimal and included mild dizziness and gastrointestinal disturbances, suggesting a favorable safety profile for long-term use .

Q. Basic: What are the recommended synthetic routes for (R)-2-(4-isopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide, and how can reaction conditions be optimized?

Methodological Answer:
The synthesis of this compound can be approached via multi-step organic reactions, leveraging methodologies analogous to structurally related acetamides. Key steps include:

• Nucleophilic substitution : Reacting a pyridine derivative (e.g., 5-(2,2,2-trifluoroethoxy)pyridin-2-amine) with an α-chloroacetamide intermediate under reflux in ethanol or acetone, as seen in similar syntheses of pyridine-linked acetamides .
• Chiral resolution : To achieve the (R)-enantiomer, chiral catalysts (e.g., palladium with chiral ligands) or enzymatic resolution may be employed.
• Optimization : Reaction parameters such as solvent polarity (e.g., ethanol vs. dimethylformamide), temperature (80–100°C), and stoichiometric ratios (1:1.2 molar ratio of amine to electrophile) significantly impact yield. Purification via column chromatography (silica gel, hexane/ethyl acetate gradient) or recrystallization (using chloroform-acetone mixtures) enhances purity (>95%) .
• Analytical validation : Confirm purity and structure using ¹H/¹³C NMR (to verify stereochemistry and functional groups) and HPLC (for enantiomeric excess determination) .

Q. Advanced: How can researchers address contradictions in reported biological activities of structurally similar acetamide derivatives?

Methodological Answer:
Discrepancies in biological data often arise from variations in:

• Compound purity : Impurities (e.g., diastereomers or unreacted intermediates) can skew results. Validate purity via LC-MS and elemental analysis .
• Assay conditions : Differences in cell lines (e.g., HEK293 vs. CHO-K1), incubation times, or buffer pH may alter activity. Standardize protocols using controls like known inhibitors/agonists.
• Structural nuances : Subtle changes (e.g., trifluoroethoxy vs. methoxy groups) drastically affect target binding. Perform structure-activity relationship (SAR) studies by synthesizing analogs with systematic substituent variations .
• Target validation : Use knockout models or RNA interference to confirm the specificity of observed effects.

Q. Advanced: What advanced techniques are critical for characterizing the stereochemistry and solid-state properties of this compound?

Methodological Answer:

• X-ray crystallography : Resolve absolute configuration and intermolecular interactions (e.g., hydrogen bonding networks) by growing single crystals via slow evaporation (solvent: chloroform/acetone) .
• Chiral HPLC : Employ columns with cellulose-based stationary phases (e.g., Chiralpak IC) and isocratic elution (hexane:isopropanol 90:10) to determine enantiomeric excess .
• Dynamic NMR : Study conformational dynamics (e.g., rotation of the isopropylphenyl group) in solution by variable-temperature ¹H NMR .
• Thermogravimetric analysis (TGA) : Assess thermal stability and decomposition pathways under nitrogen atmosphere (heating rate: 10°C/min) .

Q. Basic: What are the standard protocols for evaluating the pharmacokinetic (PK) properties of this compound in preclinical studies?

Methodological Answer:

• In vitro assays :
  • Metabolic stability : Incubate with liver microsomes (human/rat) and quantify parent compound via LC-MS/MS .
  • Plasma protein binding : Use equilibrium dialysis or ultrafiltration to measure free fraction .
• In vivo PK : Administer intravenously/orally to rodents, collect blood samples at timed intervals, and analyze plasma concentrations. Key parameters include Cₘₐₓ , t₁/₂ , and bioavailability .
• Tissue distribution : Radiolabel the compound (e.g., ¹⁴C) and track accumulation in organs using scintillation counting .

Q. Advanced: How does the trifluoroethoxy group influence the compound’s binding affinity to biological targets?

Methodological Answer:
The 2,2,2-trifluoroethoxy moiety enhances:

• Lipophilicity : Measured via logP (octanol-water partition coefficient), improving membrane permeability.
• Electron-withdrawing effects : Stabilizes hydrogen bonds with target residues (e.g., in kinase active sites). Confirmed via molecular docking (software: AutoDock Vina) and isothermal titration calorimetry (ITC) .
• Metabolic resistance : The CF₃ group reduces oxidative degradation by cytochrome P450 enzymes, as shown in hepatocyte stability assays .

Q. Basic: What strategies mitigate byproduct formation during the synthesis of this acetamide?

Methodological Answer:

• Controlled stoichiometry : Use a slight excess (10–20%) of the pyridine derivative to minimize unreacted α-chloroacetamide.
• In situ quenching : Add scavengers (e.g., polymer-bound triphenylphosphine) to trap reactive intermediates .
• Real-time monitoring : Employ FTIR to track reaction progress (e.g., disappearance of carbonyl stretches at ~1700 cm⁻¹) .

Q. Advanced: How can computational modeling guide the optimization of this compound’s selectivity for a target enzyme?

Methodological Answer:

• Molecular dynamics (MD) simulations : Simulate ligand-enzyme complexes (e.g., 100 ns trajectories) to identify critical binding residues and conformational changes .
• Free energy perturbation (FEP) : Calculate ΔΔG for substituent modifications (e.g., replacing isopropyl with cyclopropyl) to predict affinity changes .
• Pharmacophore modeling : Define essential features (e.g., hydrogen bond acceptors, hydrophobic pockets) using software like Schrödinger’s Phase .