(R)-benzyl 2-((R)-2-amino-3-phenylpropanamido)-4-methylpentanoate | 1024829-65-9

• 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
• 英文名称: (R)-benzyl 2-((R)-2-amino-3-phenylpropanamido)-4-methylpentanoate
• 英文别名: D-phenylalanyl-D-leucine benzyl ester；benzyl (2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-4-methylpentanoate
• CAS: 1024829-65-9
• 化学式: C₂₂H₂₈N₂O₃
• 分子量: 368.476
• InChiKey: WHGLYHPTKLTQMK-WOJBJXKFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-benzyl 2-((R)-2-amino-3-phenylpropanamido)-4-methylpentanoate 在 palladium on activated charcoal 、 氢气 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 potassium iodide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 benzyl 1-((9R,12R,15R)-9-benzyl-15-(4-((tert-butoxycarbonyl)amino)butyl)-12-isobutyl-2,2-dimethyl-4,7,10,13-tetraoxo-5-((R)-2-phenylpropyl)-3-oxa-5,8,11,14-tetraazahexadecan-16-oyl)-4-(((benzyloxy)carbonyl)amino)piperidine-4-carboxylate
  参考文献：
  名称：

  Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist

  摘要：

  Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation of KOR in the central nervous system (CNS) may cause sedation and anxiety. It has been reported that peripheral KOR activation produces comparable bioactivity without CNS-related side effects. Herein, we designed and synthesized a novel tetrapeptide (SHR0687), which was shown to be a highly potent KOR agonist with excellent selectivity over other opioid receptors, such as MOR and DOR. In addition, SHR0687 displayed favorable PK profiles across species, as well as robust in vivo efficacy in a rat carrageenan-induced pain model. Notably, SHR0687 exhibited negligible blood-brain barrier penetration, which was meaningful in minimizing CNS-related side effects.

  DOI：

  10.1021/acsmedchemlett.0c00287
• 作为产物：
  描述：

  Boc-D-苯丙氨酸 在 盐酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (R)-benzyl 2-((R)-2-amino-3-phenylpropanamido)-4-methylpentanoate
  参考文献：
  名称：

  Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist

  摘要：

  Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation of KOR in the central nervous system (CNS) may cause sedation and anxiety. It has been reported that peripheral KOR activation produces comparable bioactivity without CNS-related side effects. Herein, we designed and synthesized a novel tetrapeptide (SHR0687), which was shown to be a highly potent KOR agonist with excellent selectivity over other opioid receptors, such as MOR and DOR. In addition, SHR0687 displayed favorable PK profiles across species, as well as robust in vivo efficacy in a rat carrageenan-induced pain model. Notably, SHR0687 exhibited negligible blood-brain barrier penetration, which was meaningful in minimizing CNS-related side effects.

  DOI：

  10.1021/acsmedchemlett.0c00287

文献信息

• USE OF KOR AGONIST IN COMBINATION WITH MOR AGONIST IN PREPARING DRUG FOR TREATING PAIN
  申请人：JIANGSU HENGRUI MEDICINE CO., LTD.

  公开号：US20200368309A1

  公开（公告）日：2020-11-26

  Disclosed is the use of a KOR agonist in combination with a MOR agonist in preparing a drug for treating pain. The KOR agonist is selected from a compound as shown in the general formula (I), and the MOR agonist is selected from a compound as shown in the general formula (II), wherein the definitions of each substituent in the general formula (I) and (II) are the same as defined in the description.

  本发明揭示了在制备用于治疗疼痛的药物时，使用KOR激动剂与MOR激动剂的组合。其中，KOR激动剂选自通用式（I）所示的化合物，MOR激动剂选自通用式（II）所示的化合物，其中通用式（I）和（II）中每个取代基的定义与描述中定义的相同。
• 2 AND 3-SUBSTITUTED ENKEPHALINS
  申请人：G. D. Searle & Co.

  公开号：US04028319A1

  公开（公告）日：1977-06-07

  Analogs of enkephalin having agonist activity at opiate receptors are disclosed herein. These analogs are useful as analgesics, non-addicting narcotic antagonists and anti-diarrheal agents.

  在这里披露了具有阿片受体激动剂活性的脑啡肽类似物。这些类似物可用作镇痛剂、不成瘾的麻醉拮抗剂和抗腹泻剂。
• [EN] PHENYL PROPANAMIDE DERIVATIVE, AND MANUFACTURING METHOD AND PHARMACEUTICAL APPLICATION THEREOF<br/>[FR] DÉRIVÉ DE PHÉNYLPROPANAMIDE ET PROCÉDÉ DE FABRICATION ET APPLICATION PHARMACEUTIQUE ASSOCIÉE<br/>[ZH] 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用
  申请人：JIANGSU HENGRUI MEDICINE CO

  公开号：WO2017211272A1

  公开（公告）日：2017-12-14

  本发明提供了通式（I）所示的苯基丙酰胺类衍生物、其制备方法及其作为κ阿片样物质受体（KOR受体）激动剂的用途，和其在制备治疗和/或预防疼痛和疼痛相关疾病的药物中的用途。
• SALT OF A PHENYLPROPIONAMIDE DERIVATIVE AND PREPARATION METHOD THEREFOR
  申请人：Jiangsu Hengrui Medicine Co., Ltd.

  公开号：EP3722286B1

  公开（公告）日：2022-06-22
• EP3466962
  申请人：——

  公开号：——

  公开（公告）日：——