3,3-dimethyl-7-(pyrimidin-5-yl)-3,4-dihydro-2H,5′(1'H)-spiro-[naphthalene-1,4′-oxazol]-2′-amine | 1338092-83-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3,3-dimethyl-7-(pyrimidin-5-yl)-3,4-dihydro-2H,5′(1'H)-spiro-[naphthalene-1,4′-oxazol]-2′-amine
• 英文别名: 3,3-dimethyl-7-(pyrimidin-5-yl)-3,4-dihydro-2H,5'H-spiro[naphthalene-1,4-oxazol]-2'-amine；2,2-dimethyl-6-pyrimidin-5-ylspiro[1,3-dihydronaphthalene-4,4'-5H-1,3-oxazole]-2'-amine
• CAS: 1338092-83-3
• 化学式: C₁₈H₂₀N₄O
• 分子量: 308.383
• InChiKey: INXKKZAEXZKHNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  73.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  7-bromo-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one 在 四(三苯基膦)钯 、 碘 、 sodium carbonate 作用下， 以 乙醚 、 水 、 甲苯 为溶剂， 反应 13.0h， 生成 3,3-dimethyl-7-(pyrimidin-5-yl)-3,4-dihydro-2H,5′(1'H)-spiro-[naphthalene-1,4′-oxazol]-2′-amine
  参考文献：
  名称：

  Spirocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid β in a Higher Species

  摘要：

  A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (A beta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. A beta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A beta in vivo, despite efflux. Starting with spirocycle la, we explore structure activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A beta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A beta in rodents and in monkey.

  DOI：

  10.1021/jm4002154

文献信息

• [EN] COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS POUR TRAITER DES MALADIES NEURODÉGÉNÉRATIVES
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2011123674A1

  公开（公告）日：2011-10-06

  The invention provides novel spirotetrahydronaphthalene compounds of Formula α that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.

  这项发明提供了一种新型的Formula α的螺环四氢萘化合物，可以抑制APP的β-分泌酶裂解，并且可用作治疗神经退行性疾病的治疗剂。
• COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES
  申请人：Clark Christopher T.

  公开号：US20120065195A1

  公开（公告）日：2012-03-15

  The invention provides novel spirotetrahydronaphthalene compounds of Formula α that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.

  本发明提供了一种新型的螺四氢萘酚化合物，其化学式为α，可以抑制β-分泌酶对APP的切割，并且可用作治疗神经退行性疾病的治疗剂。
• Spirocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid β in a Higher Species
  作者：Kevin W. Hunt、Adam W. Cook、Ryan J. Watts、Christopher T. Clark、Guy Vigers、Darin Smith、Andrew T. Metcalf、Indrani W. Gunawardana、Michael Burkard、April A. Cox、Mary K. Geck Do、Darrin Dutcher、Allen A. Thomas、Sumeet Rana、Nicholas C. Kallan、Robert K. DeLisle、James P. Rizzi、Kelly Regal、Douglas Sammond、Robert Groneberg、Michael Siu、Hans Purkey、Joseph P. Lyssikatos、Allison Marlow、Xingrong Liu、Tony P. Tang

  DOI：10.1021/jm4002154

  日期：2013.4.25

  A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (A beta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. A beta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A beta in vivo, despite efflux. Starting with spirocycle la, we explore structure activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A beta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A beta in rodents and in monkey.