(6S,9R,12R)-6-cyclopropyl-8,9-dimethyl-12-[(4-methylphenyl)methyl]-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione | 1047666-12-5

• 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
• 英文名称: (6S,9R,12R)-6-cyclopropyl-8,9-dimethyl-12-[(4-methylphenyl)methyl]-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione
• CAS: 1047666-12-5
• 化学式: C₃₀H₄₀N₄O₄
• 分子量: 520.672
• InChiKey: ZPEDBCLQAZTDDB-RMXYQJDTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  38
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  99.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-羟基肉桂酸 在 盐酸 、 三乙基硅烷 、 三甲基氯硅烷 、 sodium azide 、 二乙基异丙基胺 、 C₂₃H₂₂NOPolS 、 palladium on activated charcoal 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 二异丁基氢化铝 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三苯基膦 、 三氟乙酸 、 potassium iodide 、 lithium chloride 、 三甲基镓 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 (6S,9R,12R)-6-cyclopropyl-8,9-dimethyl-12-[(4-methylphenyl)methyl]-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione
  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

文献信息

• MACROCYCLIC GHRELIN RECEPTOR MODULATORS AND METHODS OF USING THE SAME
  申请人：Hoveyda Hamid

  公开号：US20080194672A1

  公开（公告）日：2008-08-14

  The present invention provides novel conformationally-defined macrocyclic compounds that can function as 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, bone 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，可以作为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、骨骼疾病、遗传疾病、过度增生性疾病和炎症性疾病。
• Macrocyclic Modulators of the Ghrelin Receptor
  申请人：Marsault Eric

  公开号：US20090221689A1

  公开（公告）日：2009-09-03

  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，已被证明是生长激素释放肽受体（GHS-R1a及其亚型，同工型和变异体）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释放肽受体的激动剂，并作为治疗和预防一系列医疗状况的药物，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，遗传性疾病，高增殖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：US20110288163A1

  公开（公告）日：2011-11-24

  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.
• METHODS OF USING MACROCYCLIC AGONISTS OF THE GHRELIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL MOTILITY DISORDERS
  申请人：Fraser Graeme L.

  公开号：US20120071412A1

  公开（公告）日：2012-03-22

  The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective agonists of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Such compounds are useful as medicaments for treatment and prevention of a range of medical conditions characterized by disturbed gastrointestinal motility including, but not limited to, post-surgical gastroparesis and post-operative ileus in combination with opioid-induced bowel dysfunction. These agents are effective for multiple disorders at dose levels equivalent to those required to treat a single disorder.
• US7476653B2
  申请人：——

  公开号：US7476653B2

  公开（公告）日：2009-01-13