2-[2-(7-fluoronaphthalen-1-yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione | 1402002-39-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-[2-(7-fluoronaphthalen-1-yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione
• 英文别名: 2-{2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione；2-[2-(7-Fluoronaphthalen-1-yl)oxyethyl]-7-(4-methylimidazol-1-yl)-3,4-dihydropyrido[1,2-a]pyrazine-1,6-dione
• CAS: 1402002-39-4
• 化学式: C₂₄H₂₁FN₄O₃
• 分子量: 432.454
• InChiKey: JKYPDGRYYKKADH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  67.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-(2-chloroethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 、 7-氟萘-1-醇 在 potassium carbonate 作用下， 以 二甲基亚砜 为溶剂， 生成 2-[2-(7-fluoronaphthalen-1-yloxy)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators

  摘要：

  Herein we describe the design and synthesis of a novel series of gamma-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain A beta 42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the gamma-secretase complex, thus gaining insight into the binding site of this series of GSMs.

  DOI：

  10.1021/jm401782h

文献信息

• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• NOVEL BICYCLIC PYRIDINONES
  申请人：Pfizer Inc.

  公开号：EP2691393B1

  公开（公告）日：2016-09-14
• US8697673B2
  申请人：——

  公开号：US8697673B2

  公开（公告）日：2014-04-15
• US9067934B2
  申请人：——

  公开号：US9067934B2

  公开（公告）日：2015-06-30
• Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators
  作者：Martin Pettersson、Douglas S. Johnson、Chakrapani Subramanyam、Kelly R. Bales、Christopher W. am Ende、Benjamin A. Fish、Michael E. Green、Gregory W. Kauffman、Patrick B. Mullins、Thayalan Navaratnam、Subas M. Sakya、Cory M. Stiff、Tuan P. Tran、Longfei Xie、Liming Zhang、Leslie R. Pustilnik、Beth C. Vetelino、Kathleen M. Wood、Nikolay Pozdnyakov、Patrick R. Verhoest、Christopher J. O’Donnell

  DOI：10.1021/jm401782h

  日期：2014.2.13

  Herein we describe the design and synthesis of a novel series of gamma-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain A beta 42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the gamma-secretase complex, thus gaining insight into the binding site of this series of GSMs.