glimepiride | 261361-60-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: glimepiride
• 英文别名: 4-ethyl-3-methyl-N-[2-[4-[(4-methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide
• CAS: 261361-60-8
• 化学式: C₂₄H₃₄N₄O₅S
• 分子量: 490.624
• InChiKey: WIGIZIANZCJQQY-UHFFFAOYSA-N

物化性质

• 密度：
  1.29±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 熔点：
  207°C
• 溶解度：
  Partly miscible
• 碰撞截面：
  216.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

格列美脲据报道会经历肝脏代谢。无论是静脉注射还是口服给药后，格列美脲在CYP2C9酶的介导下经历氧化生物转化，形成主要代谢物环己基羟甲基衍生物（M1），该代谢物具有药理活性。M1可以进一步被一个或几个细胞质酶代谢为无活性的羧基衍生物（M2）。在动物模型中，M1保持了其原药约三分之一的药理活性，半衰期为3-6小时。然而，M1的降糖效果在临床上是否显著尚不清楚。

Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear.

来源:DrugBank

代谢

格列美脲已知的人类代谢物包括环己基羟甲基格列美脲。

Glimepiride has known human metabolites that include Cyclohexylhydroymethylglimepiride.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

既没有正常摄入也没有过量摄入维生素E与肝脏损伤或肝功能测试异常有关。在长期临床试验中，维生素E治疗与安慰剂相比，血清酶和胆红素升高的情况并不更频繁。实际上，在许多动物模型中，维生素E对肝脏有毒物质具有保护作用，并为肝细胞提供抗氧化和细胞保护活性。在几项随机对照试验中，发现维生素E可以改善非酒精性脂肪肝炎（NASH）患者的血清转氨酶升高和肝脏活检的脂肪变性、炎症和细胞损伤的病理学发现。治疗耐受性良好，没有病人在治疗期间出现血清转氨酶水平的显著升高或基础肝损伤的恶化。虽然肝脏组织学有所改善，包括脂肪变性、细胞损伤和炎症，但治疗并未与肝纤维化的改善相关，维生素E在非酒精性脂肪肝病长期管理中的作用尚不清楚。然而，在多项维生素E治疗的对照试验中，没有报道治疗导致显著的肝损伤或黄疸。

Neither normal nor excessively high intakes of vitamin E are associated with liver injury or liver test abnormalities. In long term clinical trials, serum enzyme and bilirubin elevations were no more frequent with vitamin E therapy than with placebo. Indeed, in many animal models, vitamin E is protective against hepatotoxic substances and provides antioxidant and cytoprotective activity to hepatocytes. In several randomized controlled trials, vitamin E has been found to improve serum aminotransferase elevations and liver biopsy histologic findings of steatosis, inflammation and cell injury in patients with nonalcoholic steatohepatitis (NASH). Therapy was well tolerated and no patients had significant rises in serum aminotransferase levels during treatment or worsening of the underlying liver injury. While liver histology improved including steatosis, cell injury and inflammation, therapy was not associated with improvements in liver fibrosis and the role of vitamin E in the long term management of nonalcoholic fatty liver disease is not clear. However, in multiple controlled trials of vitamin E therapy there have been no reports of significant liver injury or jaundice with treatment.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：格列美脲

Compound:glimepiride

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

格列美脲在口服给药后1小时内完全吸收，并呈现出线性药代动力学特征。在健康受试者单次口服格列美脲以及2型糖尿病患者多次口服给药后，血药浓度峰值（Cmax）在给药后2到3小时达到。多次给药后不会发生药物蓄积。与食物同服格列美脲时，达到Cmax的时间增加了12%，而平均血药浓度和药时曲线下面积（AUC）分别减少了8%到9%。在一项针对日本2型糖尿病患者的药代动力学研究中，每日一次给药的Cmax值高于每日两次给药的值。格列美脲的绝对生物利用度在口服给药后被认为是完全的。

Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在健康男性受试者口服格列美脲后，大约60%的总放射性在7天内通过尿液回收，其中M1和M2占尿液回收总放射性的80-90%。在两个受试者中，M1与M2的比例大约为3:2，在一个受试者中为4:1。大约40%的总放射性通过粪便回收，其中M1和M2约占放射性的70%，M1与M2的比例为1:3。尿液中或粪便中没有回收到母药。

Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，在健康受试者体内的分布容积为8.8升（113毫升/千克）。

Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg).

来源:DrugBank

吸收、分配和排泄

• 清除

单次交叉、剂量比例性（1、2、4和8毫克）在正常受试者中进行的研究以及单次和多次剂量、平行、剂量比例性（4和8毫克）在2型糖尿病患者（T2D）中进行的研究已经完成。在这些研究中，总体清除率分别为52.1 ± 16.0 mL/min，T2D患者在单次口服给药后为48.5 ± 29.3 mL/min，多次口服给药后为52.7 ± 40.3 mL/min。在健康受试者中静脉给药后，总体清除率为47.8 mL/min。

A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  glimepiride 在 烟酰胺腺嘌呤双核苷酸磷酸盐 、 magnesium chloride 作用下， 以 水 为溶剂， 生成 反式-羧基格列美脲
  参考文献：
  名称：

  Yamazaki; Tabata, Arzneimittel-Forschung/Drug Research, 1993, vol. 43, # 12, p. 1317 - 1321

  摘要：

  DOI：
• 作为产物：
  描述：

  3-乙基-2,5-二氢-4-甲基-2-氧代-n-(2-苯基乙基)-1H-吡咯-1-羧酰胺 在 氯磺酸 、 ammonium hydroxide 、 potassium carbonate 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 12.0h， 生成 glimepiride
  参考文献：
  名称：

  一种格列美脲原料药合成工艺

  摘要：

  本发明公开了一种格列美脲原料药合成工艺，以化合物A:3‑乙基‑4‑甲基‑3‑吡咯啉‑2‑酮和化合物、B:2‑苯乙基异氰酸酯为起始原料，其特征在于，中间体1的合成中，滤液套用使得中间体1的损失减少，提高了收率和生产效率；中间体2的合成中，采用氯代烃作溶剂，能大幅减少异构体杂质的产生，异构体杂质含量由8%左右降至0.5%以下，使后续工序纯化操作简单；格列美脲金属盐的合成中，采用乙腈作溶剂，使反应充分且时间大幅缩短，中间体3残留由原来的5‑10%降至0.2%以下且溶剂回收率高。本发明工艺简单和安全、生产成本低，收率高、中间体和成品质量稳定，适宜工业化大生产和有较大社会经济环保效益的降血糖药物格列美脲合成工艺。

  公开号：

  CN108383768A

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。