トログリタゾン
トログリタゾン · トログリタゾン (JAN) · rac-(R*)-3,4-ジヒドロ-2,5,7,8-テトラメチル-6-ヒドロキシ-2β*-[[4-[[(R)-2,4-ジオキソ-5β-チアゾリジニル]メチル]フェノキシ]メチル]-2H-1-ベンゾピラン · ノスカール · (R)-3,4-ジヒドロ-2,5,7,8-テトラメチル-6-ヒドロキシ-2β-[[4-[[(R)-2,4-ジオキソ-5β-チアゾリジニル]メチル]フェノキシ]メチル]-2H-1-ベンゾピラン/(S)-3,4-ジヒドロ-2,5,7,8-テトラメチル-6-ヒドロキシ-2α-[[4-[[(R)-2,4-ジオキソ-5β-チアゾリジニル]メチル]フェノキシ]メチル]-2H-1-ベンゾピラン,(1:1) · ci991 · Noscal · CS-045
識別子と物理属性
| CAS No. | 97322-87-7 |
|---|---|
| 分子式 | C24H27NO5S |
| 平均分子量 | 441.5 g/mol |
| 単同位体質量 | 441.16099396 g/mol |
| SMILES | Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2 |
| InChIKey | GXPHKUHSUJUWKP-UHFFFAOYSA-N |
| PubChem CID | 5591 |
| ChEMBL | CHEMBL408 |
| ChEBI | CHEBI:9753 |
| DTXSID | DTXSID8023719 |
| 現地名 | トログリタゾン |
化学・物理的性質
| XLogP | 5.1 |
|---|---|
| 極性表面積 | 110 |
| 水素結合供与体数 | 2 |
| 水素結合受容体数 | 6 |
| 回転可能結合数 | 5 |
| 重原子数 | 31 |
| 形式電荷 | 0 |
| 複雑度 | 681 |
| Human Drugs | FDA approved drugs -> Active ingredient |
| 融点 | 184-186 °C184-186°C |
| Collision Cross Section | 193.9 Ų [M-H]- [CCS Type: DTBuffer gas: N2Ionization: ESI-Dataset: TOXCASTSource Identifier: DTXSID8023719] |
| 沸点 | 657.0±55.0 °C(Predicted) |
| 密度 | 1.266±0.06 g/cm3(Predicted) |
| 貯蔵条件 | Inert atmosphere,Store in freezer, under -20°C |
| 溶解度 | DMSO: 20 mg/mL |
| 外観・状態 | 個体 |
| pKa（酸解離定数） | 6.34±0.50(Predicted) |
| 色 | 白から黄色 |
| 安定性 | DMSO溶液またはエタノール溶液で-20°Cで最大3か月保存できます。 |
| InChI | InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28) |
| InChIKey | GXPHKUHSUJUWKP-UHFFFAOYSA-N |
| SMILES | S1C(CC2=CC=C(OCC3(C)OC4=C(C)C(C)=C(O)C(C)=C4CC3)C=C2)C(=O)NC1=O |
| CAS データベース | 97322-87-7(CAS DataBase Reference) |
化学的特性
Crystalline Solid
安全性と法規制
| Hepatotoxicity | Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000. |
|---|---|
| 暴露経路 | Absorbed rapidly. Food increases the extent of absorption by 30% to 85%. |
| 毒性の概要 | Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPAR‘± and PPAR‘_, with a highter affinity for PPAR‘_. The drug also contains an ‘±-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-‘_B) and a concomitant increase in its inhibitor (I‘_B). NF-‘_B is an important cellular transcription regulator for the immune response. Unlike sulfonylureas, troglitazone is not an insulin secretagogue. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
用途
説明
Rezulin was launched in Japan, the UK (subseqently withdrawn) and the US for treatment of type Ⅱ diabetes. Two approaches, four steps and six steps, converge on 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman which can be elaborated in two steps to Rezulin. It is the first of a new class of thiazolidenediones for NIDDM that reduces glucose concentrations without effecting insulin secretion. It binds to peroxisome proliferator-activated receptor gamma (PPARγ) thus activating this nuclear receptor which then influences carbohydrate metabolism. This is accomplished by increasing insulin sensitivity by upregulating glucose transporter (Glut1 and/or Glut4) expression without affecting the number or affinity of insulin receptors. There is also an increase in hepatic glycogen synthase activity which enhances glucose utilization and a reduction in hepatic gluconeogenesis by inhibiting fructose-1 ,&bisphosphatase. Pancreatic islet cell destruction is prevented. It reduces serum triglycerides because PPARγ causes fibroblasts to differentiate into adipocytes and does not activate RARα. It has a half-life of 9 h and is metabolized into three compounds having no activity.
来歴
Troglitazone (Sankyo) was firstly approved 1995 in Japan and 1997 in USA and UK. It was launched in these countries in 1997. The recommended starting dose was 400 mg/d and the highest dose 600 mg. After being marketed, the daily practice revealed adverse events in the liver with cases of fatal liver failure. This lead to withdrawal of troglitazone from the market in the UK already after two months, in USA and Japan in the year 2000.
使用
Troglitazone is an an oral hypoglycemic agent which improves insulin sensitivity and decreases hepatic glucose production. Antidiabetic.
一般的な説明
A α-tocopherol (vitamin E) moiety containing thiazolidinedione class of insulin-sensitizer that acts as an activator of peroxisome proliferator-activated receptors γ (PPARγ). Also exhibits anti-proliferative and anti-inflammatory properties. Shown to induce cell cycle arrest and apoptosis in human hepatoma cells. Inhibits vascular smooth muscle cell (VSMC) migration by rapidly activating MEK/ERK pathway leading to the induction of c-fos and Ets-1 expression. Blocks PDGF-induced cell proliferation of pancreatic stellate and accelerates p21Cip1 turnover by inhibiting PKCδ signaling in VSMCs. Exerts positive inotropic effect via Ca2+ sensitization in the sarcoplasmic reticulum and inhibits Na+/H+ exchange activity and proliferation of macrovascular endothelial cells.