isopropyl 2-(2-amino-4-methylpentanamido)-6-diazo-5-ox-ohexanoate

• 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: isopropyl 2-(2-amino-4-methylpentanamido)-6-diazo-5-ox-ohexanoate
• 英文别名: propan-2-yl (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-diazo-5-oxohexanoate
• 化学式: C₁₅H₂₆N₄O₄
• 分子量: 326.396
• InChiKey: DBAUBHLOZTURGG-STQMWFEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  23
• 可旋转键数：
  11
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  isopropyl 2-(2-amino-4-methylpentanamido)-6-diazo-5-ox-ohexanoate 在 哌啶 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.17h， 生成 isopropyl (S)-2-((S)-2-(2-(2-aminoethoxy)acetamido)-4-methylpentanamido)-6-diazo-5-oxohexanoate
  参考文献：
  名称：

  [EN] DENDRIMER-GLUTAMINE ANTAGONIST CONJUGATES AND METHODS OF USE THEREOF
  [FR] CONJUGUÉS DENDRIMÈRE-GLUTAMINE ANTAGONISTE ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  已经开发出了与一种或多种谷氨酰胺拮抗剂结合的树状分子组合物，用于抑制谷氨酰胺代谢，最好是在活化的微胶质细胞中，并且使用方法用于治疗、缓解和/或预防与病原性或失调的谷氨酰胺依赖性途径和/或谷氨酸传递相关的一个或多个神经、肿瘤和/或免疫紊乱。与一种或多种谷氨酰胺拮抗剂结合的树状分子有效地抑制谷氨酰胺酶的活性，没有任何系统毒性。与一种或多种谷氨酰胺拮抗剂结合的树状分子在与受伤或患病的细胞和组织相关的活化微胶质细胞中积累。

  公开号：

  WO2022221490A1
• 作为产物：
  描述：

  5-氧代-L-脯氨酸异丙酯 在 哌啶 、 正丁基锂 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 二氯甲烷 为溶剂， 反应 31.33h， 生成 isopropyl 2-(2-amino-4-methylpentanamido)-6-diazo-5-ox-ohexanoate
  参考文献：
  名称：

  Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma

  摘要：

  The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DONs therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DONs amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.

  DOI：

  10.1021/acs.jmedchem.6b01069

文献信息

• [EN] PRODRUGS OF 6-DIAZO-5-OXO-L-NORLEUCINE<br/>[FR] PROMÉDICAMENTS DE 6-DIAZO-5-OXO-L-NORLEUCINE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2022232565A1

  公开（公告）日：2022-11-03

  The present disclosure provides prodrugs of 6-diazo-5-oxo-L-norleucine (DON) for use in treating or preventing a disease, disorder, or condition in which the inhibition of glutamineutilizing enzymes provides a benefit.

  本公开提供了6-重氮-5-氧代-L-异亮氨酸（DON）的前药，用于治疗或预防抑制谷氨酰胺利用酶有益的疾病、紊乱或状况。
• [EN] PRODRUGS OF GLUTAMINE ANALOGS<br/>[FR] PROMÉDICAMENTS D'ANALOGUES DE GLUTAMINE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2017023774A9

  公开（公告）日：2017-11-23
• GLUTAMINE ANTAGONISTS FOR THE TREATMENT OF COGNITIVE DEFICITS AND PSYCHIATRIC DISORDERS
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20180193362A1

  公开（公告）日：2018-07-12

  The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification, for use in treating cognitive deficits and/or psychiatric disorders, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND). Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
• METHODS AND COMPOSITIONS FOR TREATING METABOLIC REPROGRAMMING DISORDERS
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20180221337A1

  公开（公告）日：2018-08-09

  The disclosure provides methods of treating a condition, disease, or disorder in a subject that involves metabolically reprogrammed cells whose activation, function, growth, proliferation, or survival depends on increased activity of at least one metabolic pathway selected from the group consisting of glutamine metabolism, glycolysis, and fatty acid synthesis, comprising administering to the subject a compound having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
• METHODS FOR CANCER AND IMMUNOTHERAPY USING PRODRUGS OF GLUTAMINE ANALOGS
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20180221395A1

  公开（公告）日：2018-08-09

  The disclosure provides methods of treating cancer in a subject or preventing a relapse or reducing the incidence of relapse of cancer in a subject in remission, comprising administering to the subject: (a) a therapeutically effective amount of an immunotherapeutic agent, e.g., an immune checkpoint blockade therapy, an adoptive cellular therapy, a marrow-infiltrating lymphocytes, an adenosine A2aR inhibitor, or an antibody; and (b) a compound having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2′ , and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).