3-(1-methoxyethyl)-5-(6-methoxynaphthalen-2-yl)pyridine | 1050646-65-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(1-methoxyethyl)-5-(6-methoxynaphthalen-2-yl)pyridine
• CAS: 1050646-65-5
• 化学式: C₁₉H₁₉NO₂
• 分子量: 293.365
• InChiKey: OMFRIZLPVDHNSI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  31.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1-[5-(6-methoxynaphthalen-2-yl)pyridin-3-yl]ethanol 、 碘甲烷 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 5.0h， 以35%的产率得到3-(1-methoxyethyl)-5-(6-methoxynaphthalen-2-yl)pyridine
  参考文献：
  名称：

  Overcoming Undesirable CYP1A2 Inhibition of Pyridylnaphthalene-Type Aldosterone Synthase Inhibitors: Influence of Heteroaryl Derivatization on Potency and Selectivity

  摘要：

  Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 mu M concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.

  DOI：

  10.1021/jm800377h

文献信息

• Overcoming Undesirable CYP1A2 Inhibition of Pyridylnaphthalene-Type Aldosterone Synthase Inhibitors: Influence of Heteroaryl Derivatization on Potency and Selectivity
  作者：Ralf Heim、Simon Lucas、Cornelia M. Grombein、Christina Ries、Katarzyna E. Schewe、Matthias Negri、Barbara Birk、Rolf W. Hartmann

  DOI：10.1021/jm800377h

  日期：2008.8.1

  Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 mu M concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.