dimethyl 2-((bis{[(isopropoxycarbonyl)oxy]methoxy}phosphoryl)methyl)pentanedioate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: dimethyl 2-((bis{[(isopropoxycarbonyl)oxy]methoxy}phosphoryl)methyl)pentanedioate
• 英文别名: Dimethyl 2-[bis(propan-2-yloxycarbonyloxymethoxy)phosphorylmethyl]pentanedioate；dimethyl 2-[bis(propan-2-yloxycarbonyloxymethoxy)phosphorylmethyl]pentanedioate
• 化学式: C₁₈H₃₁O₁₃P
• 分子量: 486.41
• InChiKey: ASZMHFCCBBLFMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  32
• 可旋转键数：
  20
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  159
• 氢给体数：
  0
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  2-(diethylphosphonomethyl)-glutaric acid dimethyl ester 在 三甲基溴硅烷 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 28.0h， 生成 dimethyl 2-((bis{[(isopropoxycarbonyl)oxy]methoxy}phosphoryl)methyl)pentanedioate
  参考文献：
  名称：

  Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)

  摘要：

  2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the alpha- and gamma-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of alpha,gamma-diesters and alpha-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and a-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.

  DOI：

  10.1021/acs.jmedchem.6b00062

文献信息

• [EN] PRODRUGS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITOR<br/>[FR] PROMÉDICAMENTS D'INHIBITEUR DE L'ANTIGÈNE MEMBRANAIRE SPÉCIFIQUE DE LA PROSTATE (PSMA)
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2016022827A1

  公开（公告）日：2016-02-11

  Methods and compounds are disclosed for treating a disease or condition by inhibiting PSMA (Prostate Specific Membrane Antigen) using prodrugs of 2-PMPA.

  揭示了一种通过使用2-PMPA的前药来抑制PSMA（前列腺特异性膜抗原）来治疗疾病或症状的方法和化合物。
• Prodrugs of prostate specific membrane antigen (PSMA) inhibitor
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US10544176B2

  公开（公告）日：2020-01-28

  Methods and compounds are disclosed for treating a disease or condition by inhibiting PSMA (Prostate Specific Membrane Antigen) using prodrugs of 2-PMPA.

  本研究公开了通过使用 2-PMPA 的原药抑制 PSMA（前列腺特异性膜抗原）来治疗疾病或病症的方法和化合物。
• PRODRUGS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITOR
  申请人：The Johns Hopkins University

  公开号：EP3177632B1

  公开（公告）日：2022-01-12
• PRODRUGS OF 2-PMPA FOR HEALTHY TISSUE PROTECTION DURING PSMA-TARGETED CANCER IMAGING OR RADIOTHERAPY
  申请人：The Johns Hopkins University

  公开号：US20200069706A1

  公开（公告）日：2020-03-05

  The use of a class of prodrugs of 2-PMPA that alter tissue distribution of 2-PMPA to non-prostate tissues is disclosed. The presently disclosed prodrugs preferentially distribute to healthy tissues including the kidney, lacrimal glands, and salivary glands, which represent sites of off-target binding and toxicity for PSMA-targeted prostate cancer imaging agents and therapies. Accordingly, the 2-PMPA prodrugs can be used to pretreat, bind to, and shield the kidney and salivary glands from PSMA-targeted cytotoxic or radiotherapy.
• US9988407B2
  申请人：——

  公开号：US9988407B2

  公开（公告）日：2018-06-05