A438079 | 899507-36-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: A438079
• 英文别名: 3-[[5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine；3-((5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl)pyridine；3-[[5-(2,3-dichlorophenyl)tetrazol-1-yl]methyl]pyridine
• CAS: 899507-36-9
• 化学式: C₁₃H₉Cl₂N₅
• 分子量: 306.154
• InChiKey: MMPAULQSJLVKHP-UHFFFAOYSA-N

物化性质

• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  56.5
• 氢给体数：
  0
• 氢受体数：
  4

制备方法与用途

生物活性

A 438079 是一种有效的，选择性的 P2X7 受体拮抗剂，pIC50 值为 6.9。

靶点

pIC50: 6.9 (P2X ₇ receptor)

体外研究

In 1321N1 cells stably expressing rat P2X ₇ receptors, A 438079 blocks BzATP-(10 μM) evoked changes in intracellular calcium concentrations with an IC ₅₀ of 321 nM. A 438079 is also selective for the P2X ₇ receptor, at concentrations up to 100 μM.

体内研究

A 438079 (80 μmol/kg, i.v.) reduces noxious and innocuous evoked activity of different classes of spinal neurons in neuropathic rats. A 438079 (100 and 300 μmol/kg, i.p.) significantly raises withdrawal thresh-olds in both the SNL and CCI models. Intraperitoneal injection of A 438079 (5 and 15 mg/kg) 60 min after triggering seizures reduces seizure severity and neuronal death within the hippocampus. A 438079 has superior neuroprotective effects compared with an equally dose of phenobarbital (25 mg/kg). A 438079 partially but significantly prevents the 6-OHDA-induced depletion of striatal DA stores. Pretreatment with A 438079 reduces nociceptive behaviour scores in the HC model.

反应信息

• 作为反应物：
  描述：

  A438079 在 盐酸 作用下， 以 乙醇 为溶剂， 生成 3-[[5-(2,3-二氯苯基)-1-1H-四氮唑]甲基]吡啶盐酸盐
  参考文献：
  名称：

  WO2006/86229

  摘要：

  公开号：
• 作为产物：
  描述：

  5-(2,3-二氯苯基)-1H-四唑 、 3-(bromomethyl)pyridine hydrobromide 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 24.0h， 生成 A438079
  参考文献：
  名称：

  WO2006/86229

  摘要：

  公开号：

文献信息

• Structure−Activity Relationship Studies on a Series of Novel, Substituted 1-Benzyl-5-phenyltetrazole P2X₇ Antagonists
  作者：Derek W. Nelson、Robert J. Gregg、Michael E. Kort、Arturo Perez-Medrano、Eric A. Voight、Ying Wang、George Grayson、Marian T. Namovic、Diana L. Donnelly-Roberts、Wende Niforatos、Prisca Honore、Michael F. Jarvis、Connie R. Faltynek、William A. Carroll

  DOI：10.1021/jm051202e

  日期：2006.6.1

  1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X(7) receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X(7) cell lines

  发现1-苄基-5-芳基四唑是P2X（7）受体的新型拮抗剂。围绕苄基和苯基部分进行了结构-活性关系（SAR）研究。另外，检查了在四唑上区域化学取代的重要性。使用荧光成像酶标仪技术评估了化合物在人和大鼠重组P2X（7）细胞系中抑制钙通量的活性。还分析了类似物在人THP-1细胞中抑制IL-1β释放和抑制P2X（7）介导的孔形成的能力。化合物15d已在神经性疼痛模型中进行了功效研究，在该模型中，在不影响运动协调的剂量下观察到了机械性异常性疼痛的明显逆转。
• Use of selective P2X7 receptor antagonists
  申请人：Perez-Medrano Arturo

  公开号：US20060211739A1

  公开（公告）日：2006-09-21

  The present invention relates to the use of selective P2X 7 receptor antagonists of formula I, or a pharmaceutically acceptable salt or prodrug thereof wherein D, R 1 and R 2 are as defined in claim 1 , for the treatment of neuropathic pain, chronic inflammatory pain, inflammation, neurodegeneration and for promoting neuroregeneration,

  本发明涉及使用公式I中的选择性P2X7受体拮抗剂，或其药学上可接受的盐或前药，其中D、R1和R2如权利要求书1中定义的，用于治疗神经病理性疼痛、慢性炎性疼痛、炎症、神经退行性疾病以及促进神经再生。
• P2x7 antagonists as frontline or adjunctive treatment against status epilepticus
  申请人：Royal College of Surgeons in Ireland (RCSI)

  公开号：EP2604265A1

  公开（公告）日：2013-06-19

  P2X7 antagonists as frontline or adjunctive treatment against status epilepticus. It is shown that P2X7 antagonists can be used for frontline or adjunctive treatment for the ameloration or termination of status epilepticus and neonatal seizures, especially refractory status epilepticus or neonatal seizures. Combination with current anticonvulsants, particularly GABA-based anticonvulsants such as benzodiazepines or barbiturates, results in the effective termination of status epilepticus, even when it is refractory.

  将 P2X7 拮抗剂作为治疗癫痫状态的前线药物或辅助药物。研究表明，P2X7 拮抗剂可用于一线或辅助治疗，以缓解或终止癫痫状态和新生儿癫痫发作，尤其是难治性癫痫状态或新生儿癫痫发作。与目前的抗惊厥药（尤其是基于 GABA 的抗惊厥药，如苯二氮卓类药物或巴比妥类药物）联合使用，可有效终止癫痫状态，即使是难治性癫痫状态。
• Methods and compositions for treating alcohol use disorders
  申请人：Sanna Pietro Paolo

  公开号：US10039772B2

  公开（公告）日：2018-08-07

  Disclosed are methods and compositions for treating alcohol dependence by administration to a patient of an inhibitor of 11β-hydroxysteroid dehydrogenases (11β-HSD) to modulate glucocorticoid effects. One such compound is the 11β-HSD inhibitor carbenoxolone (18β-glycyrrhetinic acid 3β-O-hemisuccinate), which has been extensively employed in the clinic for the treatment of gastritis and peptic ulcer. Carbenoxolone is active on both 11β-HSD1 and 2 isoforms. Here, carbenoxolone is surprisingly shown to reduce both baseline and excessive drinking in rats and mice. The carbenoxolone diastereomer 18α-glycyrrhetinic acid 3β-O-hemisuccinate (αCBX), which the applicants discovered to be selective for 11β-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11β-HSD inhibitors are a new class of candidate alcohol abuse medications and existing 11β-HSD inhibitor drugs may be re-purposed for alcohol abuse treatment.

  本发明公开了通过向患者施用 11β-羟基类固醇脱氢酶（11β-HSD）抑制剂以调节糖皮质激素作用来治疗酒精依赖症的方法和组合物。其中一种化合物是 11β-HSD 抑制剂卡本诺酮（18β-甘草次酸 3β-O-hemisuccinate ），临床上已广泛用于治疗胃炎和消化性溃疡。卡贝诺酮对 11β-HSD1 和 2 同工酶均有活性。令人惊讶的是，羧甲诺龙在大鼠和小鼠体内可减少基线饮酒量和过量饮酒量。申请人发现，羧诺龙的非对映异构体 18α-甘草次酸 3β-O-hemisuccinate (αCBX)对 11β-HSD2 具有选择性，也能有效减少小鼠的饮酒量。因此，11β-HSD 抑制剂是一类新的候选酗酒药物，现有的 11β-HSD 抑制剂药物可重新用于酗酒治疗。
• P2X7 receptor antagonists for restoring T-cell lymphopoiesis in subjects infected with human immunodeficiency virus (HIV)
  申请人：INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE)

  公开号：US10548980B2

  公开（公告）日：2020-02-04

  The present invention relates to pharmaceutical composition and uses thereof for restoring T-cell lymphopoiesis in subjects infected with human immunodeficiency virus (HIV). In particular, the present invention relates to a P2X7 receptor antagonist for use in a method of restoring T-cell lymphopoiesis in a subject infected with human immunodeficiency virus (HIV) comprising administering to the subject a therapeutically effective amount of said P2X7 receptor antagonist.

  本发明涉及用于恢复感染人类免疫缺陷病毒（HIV）的受试者的T细胞淋巴细胞生成的药物组合物及其用途。特别是，本发明涉及一种P2X7受体拮抗剂，用于在感染了人类免疫缺陷病毒（HIV）的受试者中恢复T细胞淋巴细胞生成的方法，该方法包括向受试者施用治疗有效量的所述P2X7受体拮抗剂。