(S)-2-(((R)-2-(2-(3-(((benzyloxy)carbonyl)amino)propyl)phenoxy)-propyl)(tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid | 874336-36-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-2-(((R)-2-(2-(3-(((benzyloxy)carbonyl)amino)propyl)phenoxy)-propyl)(tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid
• 英文别名: (2S)-2-cyclopropyl-2-[(2-methylpropan-2-yl)oxycarbonyl-[(2R)-2-[2-[3-(phenylmethoxycarbonylamino)propyl]phenoxy]propyl]amino]acetic acid
• CAS: 874336-36-4
• 化学式: C₃₀H₄₀N₂O₇
• 分子量: 540.657
• InChiKey: AGRSMGMBBPDXAA-RLWLMLJZSA-N

物化性质

• 沸点：
  697.1±55.0 °C(Predicted)
• 密度：
  1.200±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  39
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-(((R)-2-(2-(3-(((benzyloxy)carbonyl)amino)propyl)phenoxy)-propyl)(tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid 在 二乙基异丙基胺 、 palladium 10% on activated carbon 、 氢气 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 benzyl (2R)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-[2-(3-aminopropyl)phenoxy]propyl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]-2-cyclopropylacetyl]-methylamino]propanoyl]amino]-3-(4-fluorophenyl)propanoate
  参考文献：
  名称：

  Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

  摘要：

  High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel ago fists against this G-protein coupled receptor. Early hits such as 1 (K-i = 86 nM, EC50 = 134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (K-i = 16 nM, EC50 = 29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' beta-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

  DOI：

  10.1021/jm2007062
• 作为产物：
  描述：

  L-环丙基甘氨酸甲酯盐酸盐 在 lithium hydroxide monohydrate 、 水 、 sodium carbonate 、 potassium iodide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (S)-2-(((R)-2-(2-(3-(((benzyloxy)carbonyl)amino)propyl)phenoxy)-propyl)(tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid
  参考文献：
  名称：

  Macrocyclic Modulators of the Ghrelin Receptor

  摘要：

  本发明提供了一种新颖的构象定义明确的大环化合物，已经证明是生长激素分泌素受体（GHS-R1a及其亚型、异构体和变体）的选择性调节剂。本文还描述了合成这些新型化合物的方法。这些化合物可用作生长激素分泌素受体的激动剂，用于治疗和预防一系列医疗状况，包括但不限于代谢和/或内分泌紊乱、胃肠道紊乱、心血管疾病、肥胖和与肥胖相关的疾病、中枢神经系统疾病、遗传疾病、过度增殖性疾病和炎症性疾病。

  公开号：

  US20180110824A1

文献信息

• Macrocyclic Modulators of the Ghrelin Receptor
  申请人：Ocera Therapeutics, Inc.

  公开号：US20180110824A1

  公开（公告）日：2018-04-26

  The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

  本发明提供了一种新颖的构象定义明确的大环化合物，已经证明是生长激素分泌素受体（GHS-R1a及其亚型、异构体和变体）的选择性调节剂。本文还描述了合成这些新型化合物的方法。这些化合物可用作生长激素分泌素受体的激动剂，用于治疗和预防一系列医疗状况，包括但不限于代谢和/或内分泌紊乱、胃肠道紊乱、心血管疾病、肥胖和与肥胖相关的疾病、中枢神经系统疾病、遗传疾病、过度增殖性疾病和炎症性疾病。
• Processes for intermediates for macrocyclic compounds
  申请人：Tranzyme Pharma Inc.

  公开号：US08129561B2

  公开（公告）日：2012-03-06

  The present invention is directed to novel macrocyclic compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates: wherein R1, R2, R3, R4, R5, R6, n1, m, p Z1, Z2, and Z3 are as describe in the specification. The invention also relates to compounds of formula (I) which are antagonists of the motilin receptor and are useful in the treatment of disorders associated with this receptor and with or with motility dysfunction.

  本发明涉及一种新型的大环化合物，其化学式为(I)，以及其药学上可接受的盐、水合物或溶剂化物。其中，R1、R2、R3、R4、R5、R6、n1、m、p、Z1、Z2和Z3如规范中所述。本发明还涉及化合物(I)的拮抗剂，其对胃动素受体具有拮抗作用，并可用于治疗与该受体及其运动功能障碍相关的疾病。
• Macrocyclic modulators of the ghrelin receptor
  申请人：Tranzyme Pharma, Inc.

  公开号：US07476653B2

  公开（公告）日：2009-01-13

  The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

  本发明提供了新颖的构象定义的大环化合物，已被证明是生长激素分泌肽受体（GHS-R1a和其亚型、同工异构体和变异体）的选择性调节剂。本文还描述了合成这些新化合物的方法。这些化合物可用作生长激素分泌肽受体的激动剂，用于治疗和预防一系列医疗状况，包括但不限于代谢和/或内分泌障碍、胃肠道障碍、心血管障碍、肥胖和肥胖相关疾病、中枢神经系统障碍、遗传性疾病、过度增生性疾病和炎症性疾病。
• Methods of using macrocyclic modulators of the ghrelin receptor
  申请人：Fraser Graeme L.

  公开号：US08450268B2

  公开（公告）日：2013-05-28

  The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

  本发明提供了新型构象定义的大环化合物，已经证明是生长激素分泌素受体（GHS-R1a和其亚型，异构体和变体）的选择性调节剂。本文还描述了合成新型化合物的方法。这些化合物可用作生长激素分泌素受体的激动剂，并作为治疗和预防一系列医学疾病的药物，包括但不限于代谢和/或内分泌障碍、胃肠道障碍、心血管障碍、肥胖和肥胖相关疾病、中枢神经系统障碍、遗传性疾病、增生性疾病和炎症性疾病。
• MACROCYCLIC MODULATORS OF THE GHRELIN RECEPTOR
  申请人：TRANZYME PHARMA INC.

  公开号：US20130211045A1

  公开（公告）日：2013-08-15

  The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

  本发明提供了一种新型构象定义的大环化合物，已经被证明是生长激素分泌肽受体（GHS-R1a和其亚型、同工异构体和变异体）的选择性调节剂。本文还描述了合成这些新化合物的方法。这些化合物可用作生长激素分泌肽受体的激动剂，以及用于治疗和预防一系列医学疾病，包括但不限于代谢和/或内分泌紊乱、胃肠道疾病、心血管疾病、肥胖和肥胖相关疾病、中枢神经系统疾病、遗传疾病、过度增生性疾病和炎症性疾病。