ethyl 5,7-dimethyl-3-(2-(N-methylsulfamoyl)phenyl)-4-oxo-2-((2-(piperidine-2-carbonyloxy)ethylcarbamoyloxy)methyl)-3,4-dihydroquinazoline-6-carboxylate | 1443470-19-6

• 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: ethyl 5,7-dimethyl-3-(2-(N-methylsulfamoyl)phenyl)-4-oxo-2-((2-(piperidine-2-carbonyloxy)ethylcarbamoyloxy)methyl)-3,4-dihydroquinazoline-6-carboxylate
• 英文别名: Ethyl 5,7-dimethyl-3-[2-(methylsulfamoyl)phenyl]-4-oxo-2-[2-(piperidine-2-carbonyloxy)ethylcarbamoyloxymethyl]quinazoline-6-carboxylate；ethyl 5,7-dimethyl-3-[2-(methylsulfamoyl)phenyl]-4-oxo-2-[2-(piperidine-2-carbonyloxy)ethylcarbamoyloxymethyl]quinazoline-6-carboxylate
• CAS: 1443470-19-6
• 化学式: C₃₀H₃₇N₅O₉S
• 分子量: 643.718
• InChiKey: QDIGXAOLURDGTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  45
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  190
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以58%的产率得到ethyl 5,7-dimethyl-3-(2-(N-methylsulfamoyl)phenyl)-4-oxo-2-((2-(piperidine-2-carbonyloxy)ethylcarbamoyloxy)methyl)-3,4-dihydroquinazoline-6-carboxylate
  参考文献：
  名称：

  An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB_1/2) Agonist

  摘要：

  Glaucoma is a leading cause of vision loss and blindness with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptor's CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor soluhility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.

  DOI：

  10.1021/jm4004939

文献信息

• An Effective Prodrug Strategy to Selectively Enhance Ocular Exposure of a Cannabinoid Receptor (CB_1/2) Agonist
  作者：Nello Mainolfi、James Powers、Jakal Amin、Debby Long、Wendy Lee、Margaret E. McLaughlin、Bruce Jaffee、Christopher Brain、Jason Elliott、Jeremy M. Sivak

  DOI：10.1021/jm4004939

  日期：2013.7.11

  Glaucoma is a leading cause of vision loss and blindness with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptor's CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor soluhility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.