3-吡咯烷羧酸,4-(1,3-苯并二噁唑-5-基)-1-[2-[(2,6-二乙基苯基)氨基]-2-羰基乙基]-2-(4-丙氧基苯基)-,(2R,3R,4S)- | 195529-54-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 3-吡咯烷羧酸,4-(1,3-苯并二噁唑-5-基)-1-[2-[(2,6-二乙基苯基)氨基]-2-羰基乙基]-2-(4-丙氧基苯基)-,(2R,3R,4S)-
• 英文名称: trans,trans-2-(4-propoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N-[2,6-diethylphenyl]acetamido)-pyrrolidino-3-carboxylic acid
• 英文别名: 3-Pyrrolidinecarboxylic acid, 4-(1,3-benzodioxol-5-yl)-1-(2-((2,6-diethylphenyl)amino)-2-oxoethyl)-2-(4-propoxyphenyl)-, (2R,3R,4S)-；(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)pyrrolidine-3-carboxylic acid
• CAS: 195529-54-5
• 化学式: C₃₃H₃₈N₂O₆
• 分子量: 558.675
• InChiKey: LQEHCKYYIXQEBM-FUKIBTTHSA-N

物化性质

• 沸点：
  738.3±60.0 °C(Predicted)
• 密度：
  1.233±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO: 2mg/mL, clear

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  97.3
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

生物活性

A-192621 是一种有效的非肽、口服活性、选择性内皮素 B (ETB) 受体拮抗剂，其 IC50 为 4.5 nM，Ki 为 8.8 nM。与 ETA 受体相比，A-192621 的选择性更高，IC50 值为 4280 nM，Ki 值为 5600 nM（高约 636 倍）。A-192621 促进 PASMC 细胞凋亡，并引起动脉血压升高和血浆 ET-1 水平增加。

	IC50 (nM)	Ki (nM)
ETB	4.5	8.8
ETA	4280	5600

体外研究

A-192621 (1-100 μM; 48 小时; PASMCs) 处理显著减少 PASMC 细胞的存活率，剂量依赖性明显。A-192621 (1-100 μM; 48 小时; PASMCs) 处理显著增加 PASMC 中 caspase-3/7 活性和 cleaved caspase-3 表达。A-192621 以剂量依赖性方式诱导凋亡，并增加了细胞对阿霉素处理的凋亡敏感性。

细胞活力测定

	细胞系	肺动脉平滑肌细胞（PASMCs）与阿霉素
浓度	1 μM, 10 μM, 50 μM, 100 μM
孵化时间	72 小时
结果	PASMCs 的存活率在剂量依赖性方式下显著减少

Western Blot 分析

	细胞系	肺动脉平滑肌细胞（PASMCs）与阿霉素
浓度	1 μM, 10 μM, 100 μM
孵化时间	72 小时
结果	PASMC 中 caspase-3/7 活性在剂量依赖性方式下显著增加

体内研究

A-192621 (30-100 mg/kg; 口服；每天一次；连续三天；雄性 Sprague-Dawley 大鼠) 处理抑制了 S6c 介导的 ETB 激活引起的舒血管和升压反应，ED50 值为 30 mg/kg，并未能抑制由 ETA 介导的 ET-1 引起的升压反应。A-192621 单独处理可导致清醒正常血压大鼠的动脉血压升高以及血浆中 ET-1 水平增加。

动物模型

	雄性 Sprague-Dawley 大鼠（体重 250-350 g）
剂量	30 mg/kg, 100 mg/kg
给药方式	口服；每天一次；连续三天
结果	抑制了 S6c 介导的 ETB 激活引起的舒血管和升压反应，ED50 值为 30 mg/kg。

反应信息

• 作为产物：
  描述：

  2,6-二乙基苯胺 在 sodium hydroxide 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 1.5h， 生成 3-吡咯烷羧酸,4-(1,3-苯并二噁唑-5-基)-1-[2-[(2,6-二乙基苯基)氨基]-2-羰基乙基]-2-(4-丙氧基苯基)-,(2R,3R,4S)-
  参考文献：
  名称：

  Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists. 4. Side Chain Conformational Restriction Leads to ET_B Selectivity

  摘要：

  When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.

  DOI：

  10.1021/jm990170q

文献信息

• Methods and compositions for emergency contraception using endothelin receptor antagonists
  申请人：THE POPULATION COUNCIL, INC.

  公开号：EP2246062A1

  公开（公告）日：2010-11-03

  Disclosed are methods and compositions containing endothelin receptor antagonists for emergency contraception.

  所公开的是含有内皮素受体拮抗剂的用于紧急避孕的方法和组合物。
• Compositions and methods for treating cancers associated with ETBR activation
  申请人：ENB Therapeutics, Inc.

  公开号：US10695400B2

  公开（公告）日：2020-06-30

  The description provides compositions and methods for treating ETBR-related cancer. In certain aspects, the description provides a delivery system for the controlled, systemic release of at least one of ETBR antagonists, caspase-8 inhibitors, or a combination thereof, optionally including an ETAR antagonist, an anti-PD-1 antibody, a bRAF inhibitor, niacinamide or a combination thereof. The compositions described are useful for the treatment of certain cancers, including, e.g., breast cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, as well as others. In addition, the description provides a delivery system for the controlled release of at least one of ETBR antagonists, caspase-8 inhibitors or a combination thereof, optionally including at least one of an ETAR antagonist, an anti-PD-1 antibody, a bRAF inhibitor, niacinamide, or a combination thereof, to the central nervous system that are useful for treating cancers that have spread to the brain.

  描述提供了治疗 ETBR 相关癌症的组合物和方法。在某些方面，本发明提供了一种递送系统，用于控制、全身性释放ETBR拮抗剂、caspase-8抑制剂或其组合中的至少一种，可选地包括ETAR拮抗剂、抗PD-1抗体、bRAF抑制剂、烟酰胺或其组合。所述组合物可用于治疗某些癌症，包括乳腺癌、恶性黑色素瘤、鳞状细胞癌、胶质母细胞瘤等。此外，描述还提供了一种向中枢神经系统控制释放至少一种ETBR拮抗剂、caspase-8抑制剂或其组合的递送系统，可选地包括至少一种ETAR拮抗剂、抗PD-1抗体、bRAF抑制剂、烟酰胺或其组合，该系统对治疗扩散到大脑的癌症有用。
• Therapeutic treatments using centhaquin
  申请人：MIDWESTERN UNIVERSITY

  公开号：US10828368B2

  公开（公告）日：2020-11-10

  Methods of treating hypertension, pain, and resuscitative hemorrhagic shock using an adrenergic agent, like centhaquin, are disclosed. The methods treat mammals, including humans.

  公开了使用肾上腺素能制剂（如仙人掌）治疗高血压、疼痛和抢救失血性休克的方法。这些方法可治疗哺乳动物，包括人类。
• Methods and compositions for treatment of endothelin B receptor expressing tumors
  申请人：ENB Therapeutics, Inc.

  公开号：US11338014B2

  公开（公告）日：2022-05-24

  The description provides compositions and methods for treating ETBR-related cancer. In certain aspects, the description provides a delivery system for the controlled, systemic release of at least one of ETBR antagonists, caspase-8 inhibitors, or a combination thereof, optionally including an ETAR antagonist, an anti-PD-1 antibody, a bRAF inhibitor, niacinamide or a combination thereof. The compositions described are useful for the treatment of certain cancers, including, e.g., breast cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, as well as others. In addition, the description provides a delivery system for the controlled release of at least one of ETBR antagonists, caspase-8 inhibitors or a combination thereof, optionally including at least one of an ETAR antagonist, an anti-PD-1 antibody, a bRAF inhibitor, niacinamide, or a combination thereof, to the central nervous system that are useful for treating cancers that have spread to the brain.

  描述提供了治疗 ETBR 相关癌症的组合物和方法。在某些方面，本发明提供了一种递送系统，用于控制、全身性释放ETBR拮抗剂、caspase-8抑制剂或其组合中的至少一种，可选地包括ETAR拮抗剂、抗PD-1抗体、bRAF抑制剂、烟酰胺或其组合。所述组合物可用于治疗某些癌症，包括乳腺癌、恶性黑色素瘤、鳞状细胞癌、胶质母细胞瘤等。此外，描述还提供了一种向中枢神经系统控制释放至少一种ETBR拮抗剂、caspase-8抑制剂或其组合的递送系统，可选地包括至少一种ETAR拮抗剂、抗PD-1抗体、bRAF抑制剂、烟酰胺或其组合，该系统对治疗扩散到大脑的癌症有用。
• METHODS AND COMPOSITIONS FOR EMERGENCY CONTRACEPTION USING ENDOTHELIN RECEPTOR ANTAGONISTS
  申请人：THE POPULATION COUNCIL, INC.

  公开号：EP1906987B1

  公开（公告）日：2011-01-19