azepan-2-ylmethanol hydrochloride | 66928-78-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: azepan-2-ylmethanol hydrochloride
• 英文别名: hexahydroazepin-2-yl-methanol; hydrochloride；azepan-2-ylmethanol;hydrochloride
• CAS: 66928-78-7
• 化学式: C₇H₁₅NO*ClH
• mdl: MFCD00457606
• 分子量: 165.663
• InChiKey: VGRRDVSUABPMSM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.47
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  32.3
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  azepan-2-ylmethanol hydrochloride 在 copper(l) iodide 、 三乙胺 、 sodium hydroxide 作用下， 以 二氯甲烷 、 二甲基亚砜 、 异丙醇 为溶剂， 反应 1.0h， 生成 2-(1-(4-(2,4-dichlorobenzyloxy)phenyl)azepan-2-yl)acetonitrile
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

  DOI：

  10.1021/acs.jmedchem.6b01559
• 作为产物：
  描述：

  六氢-1H-氮杂卓-1,2-二甲酸 1-叔丁酯 在 N-甲基吗啉 、 盐酸 、 sodium tetrahydroborate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 1.75h， 生成 azepan-2-ylmethanol hydrochloride
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

  DOI：

  10.1021/acs.jmedchem.6b01559

文献信息

• Structure guided design of a series of sphingosine kinase (SphK) inhibitors
  作者：Darin J. Gustin、Yihong Li、Matthew L. Brown、Xiaoshan Min、Mike J. Schmitt、Malgorzata Wanska、Xiaodong Wang、Richard Connors、Sheere Johnstone、Mario Cardozo、Alan C. Cheng、Shawn Jeffries、Brendon Franks、Shyun Li、Shanling Shen、Mariwil Wong、Holger Wesche、Guifen Xu、Timothy J. Carlson、Matthew Plant、Kurt Morgenstern、Karen Rex、Joanna Schmitt、Angela Coxon、Nigel Walker、Frank Kayser、Zhulun Wang

  DOI：10.1016/j.bmcl.2013.06.030

  日期：2013.8

  inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable

  鞘氨醇-1-磷酸（S1P）信号在有丝分裂，细胞迁移和血管生成中起着至关重要的作用。鞘氨醇激酶（SphKs）催化鞘磷脂代谢中的关键步骤，从而导致S1P的产生。SphK有两种同工型，对SphK缺陷小鼠的观察表明，这两种同工型可以弥补彼此的损失。因此，可能需要抑制两种同工型才能阻断SphK依赖性血管生成。基于结构的方法用于设计和合成一系列SphK抑制剂，从而鉴定出人类SphK两种同工型的第一种有效抑制剂。此外，据我们所知，
• Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
  作者：Elizabeth A. Jurica、Ximao Wu、Kristin N. Williams、Andres S. Hernandez、David S. Nirschl、Richard A. Rampulla、Arvind Mathur、Min Zhou、Gary Cao、Chunshan Xie、Biji Jacob、Hong Cai、Tao Wang、Brian J. Murphy、Heng Liu、Carrie Xu、Lori K. Kunselman、Michael B. Hicks、Qin Sun、Dora M. Schnur、Doree F. Sitkoff、Elizabeth A. Dierks、Atsu Apedo、Douglas B. Moore、Kimberly A. Foster、Mary Ellen Cvijic、Reshma Panemangalore、Neil A. Flynn、Brad D. Maxwell、Yang Hong、Yuan Tian、Jason J. Wilkes、Bradley A. Zinker、Jean M. Whaley、Joel C. Barrish、Jeffrey A. Robl、William R. Ewing、Bruce A. Ellsworth

  DOI：10.1021/acs.jmedchem.6b01559

  日期：2017.2.23

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.