曲前列素 | 289480-64-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 曲前列素
• 中文别名: 曲前列尼尔钠
• CAS: 289480-64-4
• 化学式: C23H34NaO5
• 分子量: 413.5
• InChiKey: RCKWZOAISRYANP-ZSESPEEFSA-N

物化性质

• 溶解度：
  二甲基亚砜：≥26 mg/ml（63.03毫摩尔）

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  87
• 氢给体数：
  3
• 氢受体数：
  5

安全信息

• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P501,P270,P202,P201,P264,P280,P308+P313,P362+P364,P301+P310+P330,P302+P352+P312,P405
• 危险品运输编号：
  2811
• 危险性描述：
  H301,H311,H331,H361

制备方法与用途

应用

吸入曲前列素钠（一种前列环素类似物）是最近获得FDA批准用于治疗致命性孤儿疾病的药物：肺动脉高压（PAH）。与安慰剂相比，曲前列环素可保留窦状内皮细胞衬里并减少移植后早期的血小板沉积。安慰剂组的肝组织血流明显受损，而曲前列环素维持血流量与正常水平相似。前列腺素治疗显着增加内皮细胞集落形成细胞与间充质干细胞在裸鼠移植的基质胶中的血管形成能力。在间充质干细胞中沉默VEGF-A基因也会阻断曲前列环素的促血管生成作用。曲前列环素在提高小鼠和人类造血干细胞和祖细胞中的细胞内cAMP水平方面最有效。与常氧小鼠相比，用曲前列环素治疗显着减少细胞募集。曲前列环素还可降低右心室收缩压并略微减少血管重塑，但无法逆转右心室肥厚。

作用机制

曲前列环素对DP1，EP2和IP受体具有高亲和力（分别为Ki = 4.4,3.6和32nM），对EP1和EP4受体的亲和力低，对EP3，FP和TP受体的亲和力甚至更低。与曲前列环素一样，IP，DP1和EP2受体的激活均可导致人肺动脉的血管舒张。前列环素抑制培养的内皮细胞集落形成细胞的活力。来自曲前列素预处理的间充质干细胞的条件培养基刺激内皮细胞集落形成细胞增殖。

生物活性

Treprostinil sodium (UT-15, Remodulin, Orenitram, Tyvaso, Trevyent) 是一种有效的 DP1、EP2 和 IP 受体的激动剂，对应的Ki值分别为4.4 nM、3.6 nM和32 nM。

靶点

Target	Value
EP2 (Cell-free assay)	3.6 nM(Ki)
DP1 (Cell-free assay)	4.4 nM(Ki)
IP (Cell-free assay)	32 nM(Ki)

体外研究

Treprostinil has high affinity for the DP1, EP2 and IP receptors (K _i =4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries.Treprostinil inhibits viability of cultured endothelial colony forming cells. Endothelial colony forming cells proliferation is stimulated by conditioned media from Treprostinil pretreated mesenchymal stem cells.

体内研究

Inhaled treprostinil sodium, a prostacyclin analog, is the most recent agent to receive FDA approval for the treatment of a fatal orphan disease: pulmonary arterial hypertension (PAH). Treprostinil preserves the sinusoidal endothelial cell lining and reduces platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow is significantly compromised in the placebo group, whereas treprostinil maintains blood flow similar to normal levels.Treprostinil treatment significantly increases the vessel-forming ability of endothelial colony forming cells combined with mesenchymal stem cells in Matrigel implanted in nude mice. Silencing VEGF-A gene in mesenchymal stem cells also blocks the pro-angiogenic effect of Treprostinil. Treprostinil is most efficacious in raising intracellular cAMP levels in murine and human hematopoietic stem and progenitor cells. Treatment with Treprostinil significantly reduces the recruitment of cells compared to normoxic mice. Treprostinil also reduces right ventricular systolic pressure and slightly reduces the vascular remodelling but fails to reverse the right ventricular hypertrophy.