Ulimorelin hydrochloride anhydrous | 874336-43-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: Ulimorelin hydrochloride anhydrous
• 英文别名: (3R,6S,9R,12R)-6-cyclopropyl-12-[(4-fluorophenyl)methyl]-3,8,9-trimethyl-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione;hydrochloride
• CAS: 874336-43-3
• 化学式: C₃₀H₃₉FN₄O₄*ClH
• 分子量: 575.123
• InChiKey: WZRLNIOAVAFOOD-UZAUECDSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.02
• 重原子数：
  40
• 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：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  乙醇 、 Ulimorelin hydrochloride anhydrous 以 水 为溶剂， 以88%的产率得到(3R,6S,9R,12R)-6-cyclopropyl-12-[(4-fluorophenyl)methyl]-3,8,9-trimethyl-2-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-7,10,13-trione;ethanol;hydrochloride
  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 盐酸 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 水 、 氢气 、 sodium carbonate 、 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-) 、 3-(二乙氧基邻酰氧基)-1,2,3-苯并三嗪-4-酮 、 potassium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.58h， 生成 Ulimorelin hydrochloride anhydrous
  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。
• [EN] SALTS, SOLVATES, AND PHARMACEUTICAL COMPOSITIONS OF MACROCYCLIC GHRELIN RECEPTOR AGONISTS AND METHODS OF USING THE SAME<br/>[FR] SELS, SOLVATES ET COMPOSITIONS PHARMACEUTIQUES D'AGONISTES MACROCYCLIQUES DU RÉCEPTEUR DE LA GHRÉLINE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：TRANZYME PHARMA INC

  公开号：WO2011041369A1

  公开（公告）日：2011-04-07

  The present invention provides novel salts and solvates of macrocyclic compounds that bind to and/or are functional agonists of the ghrelin (growth hormone secretagogue) receptor. The invention also relates to polymorphs of these salts and solvates, pharmaceutical compositions containing these salts or solvates, and methods of using the pharmaceutical compositions. These pharmaceutical compositions are useful as therapeutics for a range of disease indications, in particular, for treatment and prevention of gastrointestinal disorders including, but not limited to, postoperative ileus, gastroparesis, including diabetic and postsurgical gastroparesis, opioid bowel dysfunction, chronic intestinal pseudo-obstruction, short bowel syndrome, functional gastrointestinal disorders and gastrointestinal dysmotility, such as that occurring in conjunction with other disease states, in critical care situations or as a result of treatment with pharmaceutical agents. Additionally, the pharmaceutical compositions have application to the treatment and prevention of metabolic and/or endocrine disorders, cardiovascular disorders, central nervous system disorders, bone disorders, inflammatory disorders, hyperproliferative disorders, disorders characterized by apoptosis and genetic disorders.

  本发明提供了一种新型的大环化合物的盐和溶剂化物，它们能够结合和/或是促进ghrelin（生长激素分泌素）受体的功能。本发明还涉及这些盐和溶剂化物的多晶形态、含有这些盐或溶剂化物的制药组合物以及使用这些制药组合物的方法。这些制药组合物可用于治疗一系列疾病，特别是用于治疗和预防包括但不限于术后肠梗阻、胃排空障碍（包括糖尿病和手术后的胃排空障碍）、阿片类药物肠道功能障碍、慢性肠假性梗阻、短肠综合症、功能性胃肠疾病和胃肠动力障碍等胃肠道疾病，尤其是在其他疾病状态下、危重病情下或由于药物治疗而引起的胃肠动力障碍。此外，这些制药组合物还适用于治疗和预防代谢和/或内分泌疾病、心血管疾病、中枢神经系统疾病、骨疾病、炎症性疾病、过度增生性疾病、以细胞凋亡为特征的疾病和遗传疾病。
• Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic
  作者：Hamid R. Hoveyda、Eric Marsault、René Gagnon、Axel P. Mathieu、Martin Vézina、Annick Landry、Zhigang Wang、Kamel Benakli、Sylvie Beaubien、Carl Saint-Louis、Martin Brassard、Jean-François Pinault、Luc Ouellet、Shridhar Bhat、Mahesh Ramaseshan、Xiaowen Peng、Laurence Foucher、Sophie Beauchemin、Patrick Bhérer、Daniel F. Veber、Mark L. Peterson、Graeme L. Fraser

  DOI：10.1021/jm2007062

  日期：2011.12.22

  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.