Simeprevir
概要
説明
TMC435は、シメプレビルとしても知られており、強力な1日1回投与の非共有結合性経口型C型肝炎ウイルスNS3/4Aプロテアーゼ阻害剤です。慢性C型肝炎ウイルス1型感染症の治療には、ペグインターフェロンとリバビリンとの併用が用いられます。 この化合物は、日本、カナダ、米国、ロシア、欧州連合、メキシコ、オーストラリアなど、いくつかの国で承認されています .
作用機序
TMC435は、C型肝炎ウイルスのNS3/4Aセリンプロテアーゼを阻害することでその効果を発揮します。このプロテアーゼは、ウイルスの複製に不可欠です。この酵素を阻害することにより、TMC435はウイルスが宿主内で複製および拡散するのを防ぎます。 TMC435の分子標的は、NS3/4Aプロテアーゼ内の特定の残基であり、酵素活性に不可欠です .
類似化合物の比較
TMC435は、テラプレビルやボセプレビルなどの他のC型肝炎ウイルスNS3/4Aプロテアーゼ阻害剤と似ています。 TMC435は、これらの化合物とは異なるいくつかのユニークな特徴を持っています。たとえば、TMC435は、より有利な耐性プロファイルを持ち、より幅広いC型肝炎ウイルス遺伝子型に対して効果があります。 さらに、TMC435は、他のプロテアーゼ阻害剤と比較して、安全性と忍容性が優れていることが示されています .
類似化合物
- テラプレビル
- ボセプレビル
- グラゾプレビル
- パリタプレビル
生化学分析
Biochemical Properties
Simeprevir plays a crucial role in inhibiting the replication of the hepatitis C virus by targeting the NS3/4A protease, an enzyme essential for the viral life cycle. The compound binds non-covalently to the NS3/4A protease, resulting in a fast association and slow dissociation rate . This interaction prevents the protease from cleaving the HCV polyprotein into functional viral proteins, thereby inhibiting viral replication. This compound also interacts with other biomolecules, such as the cofactor N4A subunit, which is part of the NS3/4A heterodimeric complex .
Cellular Effects
This compound exerts significant effects on various types of cells, particularly hepatocytes, where it accumulates after uptake via organic anion-transporting polypeptides OATP1B1 and OATP1B3 . In hepatocytes, this compound inhibits the NS3/4A protease, leading to a reduction in viral replication. This inhibition affects cell signaling pathways, gene expression, and cellular metabolism by preventing the production of viral proteins necessary for the virus’s life cycle . Additionally, this compound has been shown to display synergistic effects with interferon-α and HCV NS5B inhibitors, further enhancing its antiviral activity .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to the NS3/4A protease, a critical enzyme for the hepatitis C virus. By inhibiting this protease, this compound prevents the cleavage of the HCV polyprotein into individual viral proteins, thereby blocking viral replication . This compound’s binding interactions with the NS3/4A protease are highly specific and potent, making it an effective antiviral agent. Additionally, this compound’s resistance profile differs from first-generation protease inhibitors, as it is less effective against certain polymorphic variants of the NS3 protease .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound have been observed to change over time. The compound is relatively stable, with a half-life of approximately 41 hours in individuals with HCV . Over time, this compound’s antiviral activity can be influenced by factors such as drug degradation and the development of viral resistance. Long-term studies have shown that this compound maintains its efficacy in reducing viral load and achieving sustained virological response (SVR) when used in combination with other antiviral agents .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. Studies have shown that higher doses of this compound result in more significant reductions in viral replication and improved treatment outcomes . At very high doses, this compound may exhibit toxic or adverse effects, such as hepatotoxicity. It is essential to determine the optimal dosage that maximizes antiviral efficacy while minimizing potential side effects .
Metabolic Pathways
This compound is primarily metabolized in the liver by the cytochrome P450 enzyme CYP3A4, with minor contributions from CYP2C8 and CYP2C19 . The metabolic pathways of this compound involve its conversion into various metabolites, which are then excreted from the body. The compound’s interaction with these enzymes can affect metabolic flux and metabolite levels, influencing its overall efficacy and safety profile .
Transport and Distribution
This compound is transported and distributed within cells and tissues through specific transporters and binding proteins. The compound is taken up into hepatocytes via organic anion-transporting polypeptides OATP1B1 and OATP1B3, where it accumulates and exerts its antiviral effects . This compound’s localization within hepatocytes is crucial for its activity, as it needs to reach the NS3/4A protease to inhibit viral replication effectively .
Subcellular Localization
The subcellular localization of this compound is primarily within the cytoplasm of hepatocytes, where it interacts with the NS3/4A protease . The compound’s activity and function are influenced by its localization, as it needs to be in proximity to the viral protease to exert its inhibitory effects. Post-translational modifications and targeting signals may also play a role in directing this compound to specific compartments within the cell .
準備方法
TMC435の調製には、いくつかの合成経路と反応条件が伴います。合成における重要な中間体の1つは、二環性ラクトンアミドです。 この中間体の調製方法は、大環状化合物の形成を含む複数の段階を伴います . TMC435の工業生産は、通常、医薬品用途に適した安定で純粋な形態を得るために化合物を結晶化することによって行われます .
化学反応の分析
TMC435は、酸化、還元、置換など、さまざまな化学反応を受けます。これらの反応で一般的に使用される試薬には、有機溶媒、酸、塩基があります。 これらの反応から生成される主な生成物は、通常、元の化合物の誘導体であり、薬理学的な特性が異なる場合があります .
科学研究用途
TMC435は、幅広い科学研究用途を持っています。主に慢性C型肝炎ウイルス感染症の治療に使用されます。この化合物は、その有効性、安全性、薬物動態を評価するために、臨床試験で広く研究されてきました。 さらに、TMC435は、C型肝炎ウイルスの耐性プロファイルを理解し、新しい抗ウイルス療法を開発するための研究にも使用されています .
科学的研究の応用
TMC435 has a wide range of scientific research applications. It is primarily used in the treatment of chronic hepatitis C virus infection. The compound has been extensively studied in clinical trials to evaluate its efficacy, safety, and pharmacokinetics. Additionally, TMC435 is used in research to understand the resistance profile of hepatitis C virus and to develop new antiviral therapies .
類似化合物との比較
TMC435 is similar to other hepatitis C virus NS3/4A protease inhibitors, such as telaprevir and boceprevir. TMC435 has several unique features that distinguish it from these compounds. For example, TMC435 has a more favorable resistance profile and is effective against a broader range of hepatitis C virus genotypes. Additionally, TMC435 has been shown to have a better safety and tolerability profile compared to other protease inhibitors .
Similar Compounds
- Telaprevir
- Boceprevir
- Grazoprevir
- Paritaprevir
特性
CAS番号 |
923604-59-5 |
|---|---|
分子式 |
C38H47N5O7S2 |
分子量 |
749.9 g/mol |
IUPAC名 |
(4S)-N-cyclopropylsulfonyl-17-[7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxamide |
InChI |
InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/t23?,24?,27?,28?,38-/m0/s1 |
InChIキー |
JTZZSQYMACOLNN-ZMKZURCUSA-N |
SMILES |
CC1=C(C=CC2=C1N=C(C=C2OC3CC4C(C3)C(=O)N(CCCCC=CC5CC5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)C7=NC(=CS7)C(C)C)OC |
異性体SMILES |
CC1=C(C=CC2=C1N=C(C=C2OC3CC4C(C3)C(=O)N(CCCCC=CC5C[C@@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)C7=NC(=CS7)C(C)C)OC |
正規SMILES |
CC1=C(C=CC2=C1N=C(C=C2OC3CC4C(C3)C(=O)N(CCCCC=CC5CC5(NC4=O)C(=O)NS(=O)(=O)C6CC6)C)C7=NC(=CS7)C(C)C)OC |
Color/Form |
White to almost white powder |
ピクトグラム |
Irritant; Environmental Hazard |
溶解性 |
Insoluble Practically insoluble in water over a wide pH range Practically insoluble in propylene glycol; very slightly soluble in ethanol; slightly soluble in acetone. Soluble in dichloromethane; freely soluble in some organic solvents |
同義語 |
435, TMC 435350, TMC N-(17-(2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3.0.04,6)octadec-7-ene-4-carbonyl)(cyclopropyl)sulfonamide Olysio simeprevir TMC 435 TMC 435350 TMC-435 TMC-435350 TMC435 TMC435350 |
蒸気圧 |
5.9X10-27 mm Hg at 25 °C (est) |
製品の起源 |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
試験管内研究製品の免責事項と情報
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