(R)-benzyl 2-((R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-4-methylpentanoate | 1024829-63-7

• 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-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-4-methylpentanoate
• 英文别名: Boc-D-Phe-D-Leu-OBn；benzyl (2R)-4-methyl-2-[[(2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]pentanoate
• CAS: 1024829-63-7
• 化学式: C₂₇H₃₆N₂O₅
• 分子量: 468.593
• InChiKey: FEMWDIOHJHEVMJ-DHIUTWEWSA-N

物化性质

• 沸点：
  631.4±55.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  34
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-benzyl 2-((R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-4-methylpentanoate 在 盐酸 、 (R)-benzyl 4-methyl-2-((R)-3-phenyl-2-(2-(((1-phenylcyclopropyl)methyl)amino) acetamido)propanamido)pentanoate 、 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 4.0h， 生成 (9R,12R)-benzyl 9-benzyl-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-5-phenylethyl-3-oxa -5,8,11-triazatridecan-13-oate
  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 、 D-亮氨酸苄酯对甲苯磺酸盐 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 以88%的产率得到(R)-benzyl 2-((R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)-4-methylpentanoate
  参考文献：
  名称：

  Synthetic peptide amides

  摘要：

  该发明涉及合成肽酰胺配体与kappa阿片受体，特别是kappa阿片受体激动剂，表现出低的P450 CYP抑制作用和低的脑内渗透性。该发明的合成肽酰胺符合以下结构的结构：含有这些化合物的药物组合物在预防和治疗与多种疾病和病况相关的疼痛和炎症方面是有用的。这种可治疗的疼痛包括内脏疼痛、神经病性疼痛和过敏症。与疾病如炎症性肠病和肠易激综合症、眼部和耳部炎症、其他疾病和病况如瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼相关的炎症可以通过该发明的药物组合物进行治疗或预防。

  公开号：

  US07402564B1

文献信息

• Synthetic peptide amides
  申请人：Cara Therapeutics, Inc.

  公开号：US07402564B1

  公开（公告）日：2008-07-22

  The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure of formula I: Pharmaceutical compositions containing these compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions. Such treatable pain includes visceral pain, neuropathic pain and hyperalgesia. Inflammation associated with conditions such as IBD and IBS, ocular and otic inflammation, other disorders and conditions such as pruritis, edema, hyponatremia, hypokalemia, ileus, tussis and glaucoma are treatable or preventable with the pharmaceutical compositions of the invention.

  该发明涉及合成肽酰胺配体与kappa阿片受体，特别是kappa阿片受体激动剂，表现出低的P450 CYP抑制作用和低的脑内渗透性。该发明的合成肽酰胺符合以下结构的结构：含有这些化合物的药物组合物在预防和治疗与多种疾病和病况相关的疼痛和炎症方面是有用的。这种可治疗的疼痛包括内脏疼痛、神经病性疼痛和过敏症。与疾病如炎症性肠病和肠易激综合症、眼部和耳部炎症、其他疾病和病况如瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼相关的炎症可以通过该发明的药物组合物进行治疗或预防。
• SYNTHETIC PEPTIDE AMIDES
  申请人：Schteingart Claudio D.

  公开号：US20090075907A1

  公开（公告）日：2009-03-19

  The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P 450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure of formula I: Pharmaceutical compositions containing these compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions. Such treatable pain includes visceral pain, neuropathic pain and hyperalgesia. Inflammation associated with conditions such as IBD and IBS, ocular and otic inflammation, other disorders and conditions such as pruritis, edema, hyponatremia, hypokalemia, ileus, tussis and glaucoma are treatable or preventable with the pharmaceutical compositions of the invention.

  本发明涉及合成肽酰胺类κ-阿片受体配体，特别涉及表现出低P450CYP抑制和低脑内渗透的κ-阿片受体激动剂。本发明的合成肽酰胺符合公式I的结构：含有这些化合物的药物组合物在预防和治疗与各种疾病和病况相关的疼痛和炎症方面非常有用。这种可治疗的疼痛包括脏器疼痛，神经病理性疼痛和过度疼痛反应。与条件，如炎症相关的炎症，眼部和耳部炎症，其他疾病和病况，如瘙痒，水肿，低钠血症，低钾血症，肠梗阻，咳嗽和青光眼，均可通过本发明的药物组合物得到治疗或预防。
• SYNTHETIC PEPTIDE AMIDES AND DIMERIC FORMS THEREOF
  申请人：Schteingart Claudio D.

  公开号：US20100075910A1

  公开（公告）日：2010-03-25

  The invention relates to synthetic peptide amides that are ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P 450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure: wherein Xaa is a D-amino acid and G is selected from the following three groups: The compounds are useful in the prophylaxis and treatment of pain, pruritus and inflammation associated with a variety of diseases and conditions.

  本发明涉及合成的肽酰胺，它们是kappa阿片受体的配体，特别是kappa阿片受体的激动剂，表现出低的P450CYP抑制和低的进入大脑的能力。本发明的合成肽酰胺符合以下结构：其中Xaa是D-氨基酸，G选择自以下三个组：这些化合物在预防和治疗与各种疾病和情况相关的疼痛、瘙痒和炎症方面非常有用。
• USES OF KAPPA OPIOID SYNTHETIC PEPTIDE AMIDES
  申请人：Schteingart Claudio D.

  公开号：US20110212882A1

  公开（公告）日：2011-09-01

  The invention relates to methods of use of synthetic peptide amides that are ligands of the kappa opioid receptor in the treatment and prevention of kappa opioid receptor-associated diseases and conditions; and particularly to uses of these agonists in the prophylaxis, inhibition and treatment of pain, inflammation and pruritis associated with a variety of diseases, disorders and conditions. Inflammatory conditions preventable or treatable by the methods of the invention include diseases and conditions associated with elevated levels of a proinflammatory cytokines, such as TNF-α, IL-β, IL-6, MMP-1 and MMP-3. Such diseases and conditions include cardiovascular inflammation, neurological inflammation, skeletal inflammation, muscular inflammation, gastrointestinal inflammation, ocular inflammation, otic inflammation, inflammation due to insect bites and inflammation due to wound healing; atherosclerosis, ischemia, restenosis and vasculitis; of asthma, Sjogren's syndrome, pulmonary inflammation, chronic airway inflammation and chronic obstructive pulmonary disease (COPD), allergy, psoriasis, psoriatic arthritis, eczema, scleroderma, atopic dermatitis and systemic lupus erythematosus, arthritis, synovitis, osteomyelitis, rheumatoid arthritis, osteoarthritis and ankylosing spondylitis; septicemia and septic shock, diabetes, glucose intolerance, insulin resistance and obesity, colitis, ulcerative colitis, Crohn's disease, IBD and IBS, and the inflammatory diseases and conditions due to tumor proliferation, tumor metastasis or transplantation rejection.

  本发明涉及使用合成肽酰胺作为κ-阿片受体配体在预防和治疗κ-阿片受体相关疾病和病况中的方法；特别是在预防、抑制和治疗与多种疾病、障碍和病况相关的疼痛、炎症和瘙痒方面使用这些激动剂。本发明方法可预防或治疗与促炎性细胞因子水平升高有关的炎症疾病和病况，如TNF-α、IL-β、IL-6、MMP-1和MMP-3。这些疾病和病况包括心血管炎症、神经炎症、骨骼炎症、肌肉炎症、胃肠炎症、眼部炎症、耳部炎症、由昆虫叮咬引起的炎症和由伤口愈合引起的炎症；动脉粥样硬化、缺血、再狭窄和血管炎；哮喘、Sjogren综合症、肺部炎症、慢性气道炎症和慢性阻塞性肺病（COPD）、过敏、银屑病、银屑病性关节炎、湿疹、硬皮病、特应性皮炎和系统性红斑狼疮、关节炎、滑膜炎、骨髓炎、类风湿性关节炎、骨关节炎和强直性脊柱炎；败血症和感染性休克、糖尿病、葡萄糖不耐受、胰岛素抵抗和肥胖、结肠炎、溃疡性结肠炎、克罗恩病、炎症性肠病和肠易激综合症，以及由肿瘤增殖、肿瘤转移或移植排斥引起的炎症疾病和病况。
• SYNTHETIC PEPTIDE AMIDES AND DIMERS THEREOF
  申请人：Schteingart Claudio D.

  公开号：US20110257105A1

  公开（公告）日：2011-10-20

  The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P 450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure: The compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions.

  本发明涉及合成的肽酰胺κ阿片受体配体，特别是表现出低P450CYP抑制和低穿透脑血屏障的κ阿片受体激动剂。本发明的合成肽酰胺符合以下结构：该化合物在预防和治疗与多种疾病和病况相关的疼痛和炎症方面非常有用。