Cam-4562

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Cam-4562
• 英文别名: [(2R)-2-[[(2R)-2-(1-Benzofuran-2-ylmethoxycarbonylamino)-3-(1H-indol-3-yl)-2-methylpropanoyl]amino]-2-phenylethyl] 2-(dimethylamino)acetate
• 化学式: C₃₄H₃₆N₄O₆
• 分子量: 596.683
• InChiKey: JDKQEZNPCLGJMA-ZBWWXOROSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  44
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  N,N-二甲基甘氨酸 、 Cam-4451 在 4-二甲氨基吡啶 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以45%的产率得到Cam-4562
  参考文献：
  名称：

  摘要：

  Purpose. The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.Methods. Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pn and targeted intestinal brush-border membrane enzymes fur reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.Results. Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate predrug.Conclusions. Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.

  DOI：

  10.1023/a:1011969808907