N-{3-[(2R,3R)-5-amino-2-fluoro-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide | 1352416-52-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-{3-[(2R,3R)-5-amino-2-fluoro-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide
• 英文别名: N-[3-[(2R,3R)-5-amino-2-fluoro-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide
• CAS: 1352416-52-4
• 化学式: C₁₇H₁₅ClF₂N₄O₂
• 分子量: 380.782
• InChiKey: HBJCZLYQYZGGRO-DLBZAZTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (5R,6R)-5-(5-bromo-2-fluorophenyl)-6-fluoro-5-methyl-2,6-dihydro-1,4-oxazin-3-amine 在 copper(l) iodide 、 sodium azide 、 sodium carbonate 、 N,N-二甲基乙二胺 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 7.0h， 生成 N-{3-[(2R,3R)-5-amino-2-fluoro-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide
  参考文献：
  名称：

  1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

  摘要：

  1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pK(a) while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF A beta levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

  DOI：

  10.1021/acs.jmedchem.5b01101

文献信息

• 1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads
  作者：Frederik J. R. Rombouts、Gary Tresadern、Oscar Delgado、Carolina Martínez-Lamenca、Michiel Van Gool、Aránzazu García-Molina、Sergio A. Alonso de Diego、Daniel Oehlrich、Hana Prokopcova、José Manuel Alonso、Nigel Austin、Herman Borghys、Sven Van Brandt、Michel Surkyn、Michel De Cleyn、Ann Vos、Richard Alexander、Gregor Macdonald、Dieder Moechars、Harrie Gijsen、Andrés A. Trabanco

  DOI：10.1021/acs.jmedchem.5b01101

  日期：2015.10.22

  1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pK(a) while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF A beta levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.