6-fluoro-2-methyl-3-(4-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-4(3H)-quinazolinone | 1044749-70-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-fluoro-2-methyl-3-(4-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-4(3H)-quinazolinone
• 英文别名: 6-fluoro-2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]quinazolin-4-one
• CAS: 1044749-70-3
• 化学式: C₂₂H₂₄FN₃O₂
• 分子量: 381.45
• InChiKey: GTXKLRFKMWCBRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  45.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-氟-2-甲基-4H-苯并[d][1,3]恶嗪-4-酮 、 1-{3-[(4-aminophenyl)oxy]propyl}pyrrolidine ditosylate 在 sodium acetate 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 以39%的产率得到6-fluoro-2-methyl-3-(4-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-4(3H)-quinazolinone
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Biological Profiles of a Quinazolinone Class of Histamine H₃ Receptor Inverse Agonists

  摘要：

  A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H(3) receptor inverse agonists. 2-Methyl-3-(4-{[3-(1-pyrrolidinyl)propy]oxy}phenyl)-5-(trifluoromethyl)-4(3H)-quinazolinone (1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of I between human and rodent P-gps, the observed rodent brain permeability of I is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.

  DOI：

  10.1021/jm8003834

文献信息

• Synthesis, Structure−Activity Relationships, and Biological Profiles of a Quinazolinone Class of Histamine H₃ Receptor Inverse Agonists
  作者：Tsuyoshi Nagase、Takashi Mizutani、Shiho Ishikawa、Etsuko Sekino、Takahide Sasaki、Takashi Fujimura、Sayaka Ito、Yuko Mitobe、Yasuhisa Miyamoto、Ryo Yoshimoto、Takeshi Tanaka、Akane Ishihara、Norihiro Takenaga、Shigeru Tokita、Takehiro Fukami、Nagaaki Sato

  DOI：10.1021/jm8003834

  日期：2008.8.1

  A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H(3) receptor inverse agonists. 2-Methyl-3-(4-[3-(1-pyrrolidinyl)propy]oxy}phenyl)-5-(trifluoromethyl)-4(3H)-quinazolinone (1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of I between human and rodent P-gps, the observed rodent brain permeability of I is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.