1-(2-吡咯烷-1-基乙基)吲唑-6-胺 | 848779-64-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 中文名称: 1-(2-吡咯烷-1-基乙基)吲唑-6-胺
• 英文名称: 1-(2-pyrrolidin-1-ylethyl)-1H-indazol-6-ylamine
• 英文别名: 1-(2-Pyrrolidin-1-YL-ethyl)-1H-indazol-6-ylamine；1-(2-pyrrolidin-1-ylethyl)indazol-6-amine
• CAS: 848779-64-6
• 化学式: C₁₃H₁₈N₄
• 分子量: 230.313
• InChiKey: DEPUWRJBHNPKNE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  47.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2-吡咯烷-1-基乙基)吲唑-6-胺 、 Boc-beta-丙氨酸 在 ethyldimethylpropylcarbodiimide hydrochloride 、 1-羟基苯并三唑 、 盐酸 作用下， 以 DMF (N,N-dimethyl-formamide) 、 1,4-二氧六环 为溶剂， 反应 20.0h， 生成 3-amino-N-[1-(2-pyrrolidin-1-ylethyl)indazol-6-yl]propanamide
  参考文献：
  名称：

  Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor

  摘要：

  本发明涉及通过黑色素浓缩激素受体对黑色素浓缩激素（MCH）效应的拮抗，该拮抗对预防或治疗进食障碍、体重增加、肥胖、生殖和性行为异常、甲状腺激素分泌、利尿和水/电解质平衡、感觉处理、记忆、睡眠、唤醒、焦虑、抑郁、癫痫、神经退行性疾病和精神疾病有用。

  公开号：

  US20050137243A1
• 作为产物：
  描述：

  2-氨基-4-硝基甲苯 在 铁粉 、 potassium carbonate 、 氯化铵 、 溶剂黄146 、 sodium nitrite 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-(2-吡咯烷-1-基乙基)吲唑-6-胺
  参考文献：
  名称：

  Screening for Cardiovascular Safety:  A Structure−Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists

  摘要：

  An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor I (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (> 40 mu M) and brain (> 20 mu g/g) with < 15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHrl antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

  DOI：

  10.1021/jm0512286

文献信息

• Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity
  作者：Andrew J. Souers、Ju Gao、Dariusz Wodka、Andrew S. Judd、Mathew M. Mulhern、James J. Napier、Michael E. Brune、Eugene N. Bush、Sevan J. Brodjian、Brian D. Dayton、Robin Shapiro、Lisa E. Hernandez、Kennan C. Marsh、Hing L. Sham、Christine A. Collins、Philip R. Kym

  DOI：10.1016/j.bmcl.2005.03.114

  日期：2005.6

  was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.

  合成了一系列基于尿素的N-1-（2-氨基乙基）-吲唑，并在结合和功能试验中评估了其对黑色素浓缩激素受体1（MCHr1）的拮抗作用。鉴定了几种充当MCHr1拮抗剂的化合物，在饮食引起的肥胖小鼠体重减轻的慢性模型中，优化后得到了一种具有出色的结合亲和力，良好的功能效价和口服功效的化合物。
• Identification of 2-(4-Benzyloxyphenyl)-<i>N</i>- [1-(2-pyrrolidin-1-yl-ethyl)-1<i>H</i>-indazol-6-yl]acetamide, an Orally Efficacious Melanin-Concentrating Hormone Receptor 1 Antagonist for the Treatment of Obesity
  作者：Andrew J. Souers、Ju Gao、Michael Brune、Eugene Bush、Dariusz Wodka、Anil Vasudevan、Andrew S. Judd、Mathew Mulhern、Sevan Brodjian、Brian Dayton、Robin Shapiro、Lisa E. Hernandez、Kennan C. Marsh、Hing L. Sham、Christine A. Collins、Philip R. Kym

  DOI：10.1021/jm0490890

  日期：2005.3.1

  Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHrl) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHrl and a potent inhibitor of MCH-mediated Ca2+ release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHrl antagonist that is efficacious upon oral dosing in a chronic model of weight loss.(1)
• US7071182B2
  申请人：——

  公开号：US7071182B2

  公开（公告）日：2006-07-04
• Screening for Cardiovascular Safety:  A Structure−Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists
  作者：Philip R. Kym、Andrew J. Souers、Thomas J. Campbell、John K. Lynch、Andrew S. Judd、Rajesh Iyengar、Anil Vasudevan、Ju Gao、Jennifer C. Freeman、Dariusz Wodka、Mathew Mulhern、Gang Zhao、Seble H. Wagaw、James J. Napier、Sevan Brodjian、Brian D. Dayton、Regina M. Reilly、Jason A. Segreti、Ryan M. Fryer、Lee C. Preusser、Glenn A. Reinhart、Lisa Hernandez、Kennan C. Marsh、Hing L. Sham、Christine A. Collins、James S. Polakowski

  DOI：10.1021/jm0512286

  日期：2006.4.1

  An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor I (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (> 40 mu M) and brain (> 20 mu g/g) with < 15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHrl antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.
• Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
  申请人：Souers J. Andrew

  公开号：US20050137243A1

  公开（公告）日：2005-06-23

  The present invention relates to the antagonism of the effects of melanin-concentrating hormone (MCH) through the melanin concentrating hormone receptor which is useful for the prevention or treatment of eating disorders, weight gain, obesity, abnormalities in reproduction and sexual behavior, thyroid hormone secretion, diuresis and water/electrolyte homeostasis, sensory processing, memory, sleeping, arousal, anxiety, depression, seizures, neurodegeneration and psychiatric disorders.

  本发明涉及通过黑色素浓缩激素受体对黑色素浓缩激素（MCH）效应的拮抗，该拮抗对预防或治疗进食障碍、体重增加、肥胖、生殖和性行为异常、甲状腺激素分泌、利尿和水/电解质平衡、感觉处理、记忆、睡眠、唤醒、焦虑、抑郁、癫痫、神经退行性疾病和精神疾病有用。