benzyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethylcarbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethylcarbamate
• 英文别名: benzyl N-[1-bis(4-acetamidophenoxy)phosphoryl-2-[4-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]phenyl]ethyl]carbamate
• 化学式: C₄₃H₅₁N₆O₁₁P
• 分子量: 858.885
• InChiKey: OFNJPRDIJLBKSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  61
• 可旋转键数：
  20
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  221
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  benzyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethylcarbamate 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 8.0h， 生成 di(4-acetamidophenyl) 1-amino-2-{4-[N,N'-bis(tert-butyloxycarbonyl)guanidino]phenyl}ethanephosphonate
  参考文献：
  名称：

  Diphenyl Phosphonate Inhibitors for the Urokinase-Type Plasminogen Activator:  Optimization of the P4 Position

  摘要：

  This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC50 of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.

  DOI：

  10.1021/jm060622g
• 作为产物：
  描述：

  tert-butyl N-[4-(2-oxoethyl)phenyl]carbamate 在 三乙胺 、 三氟乙酸酐 、 yttrium(III) trifluoromethanesulfonate 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 4.0h， 生成 benzyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-(N,N'-bis(tert-butyloxycarbonyl)guanidino)phenyl)ethylcarbamate
  参考文献：
  名称：

  选择性丝氨酸蛋白酶 uPA 抑制剂 UAMC-00050 的改进合成，一种用于治疗干眼症的先导化合物

  摘要：

  α-氨基膦酸盐 UAMC-00050 是一种新开发的胰蛋白酶样丝氨酸蛋白酶抑制剂，是治疗干眼症和眼部炎症的先导化合物。安特卫普大学开发的药物化学路线存在一些阻碍扩大规模的问题，例如某些步骤的收率低、危险试剂和环境足迹。在此，我们报告了 UAMC-00050 的优化路线，其中排除了对环境不友好的溶剂，将危险试剂替换为更安全的替代品，并且在原子经济方面更有效。每个反应步骤都进行了优化以达到更高的收率，并通过实验设计在最后一步找到最佳条件。此外，所有中间体的快速色谱纯化都被塞滤取代，浆液纯化或结晶。总产率从药物化学路线中的 3% 提高到工艺开发路线中的 22%。

  DOI：

  10.1021/acs.oprd.2c00244

文献信息

• Novel Urokinase Inhibitors
  申请人：Augustyns Koen

  公开号：US20080312191A1

  公开（公告）日：2008-12-18

  The present invention relates to novel compounds with inhibitory activity towards urokinase plasminogen activator (uPA); to methods for preparation of said uPA inhibitor compounds; to pharmaceutical compositions comprising said uPA inhibitor compounds; to the use of said uPA inhibitor compounds as a medicament and the use of said uPA inhibitor compounds for the preparation of a medicament for the treatment of conditions chosen from the group comprising cancer, tumour growth, tumour invasion, tumour metastasis, diabetic retinopathy, hemorrhagic atherosclerosis and inflammatory conditions, such as rheumatoid arthritis and psoriasis.

  本发明涉及具有抑制尿激酶纤溶酶原活化物（uPA）活性的新化合物；制备所述uPA抑制剂化合物的方法；包括所述uPA抑制剂化合物的药物组合物；将所述uPA抑制剂化合物用作药物的用途以及将所述uPA抑制剂化合物用于制备用于治疗癌症、肿瘤生长、肿瘤侵袭、肿瘤转移、糖尿病视网膜病变、出血性动脉粥样硬化和类风湿性关节炎和银屑病等条件的药物的用途。
• Diphenyl Phosphonate Inhibitors for the Urokinase-Type Plasminogen Activator:  Optimization of the P4 Position
  作者：Jurgen Joossens、Pieter Van der Veken、Georgiana Surpateanu、Anne-Marie Lambeir、Ibrahim El-Sayed、Omar M. Ali、Koen Augustyns、Achiel Haemers

  DOI：10.1021/jm060622g

  日期：2006.9.1

  This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC50 of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.
• NOVEL UROKINASE INHIBITORS
  申请人：Universiteit Antwerpen

  公开号：EP1940856B1

  公开（公告）日：2014-10-08
• US8003627B2
  申请人：——

  公开号：US8003627B2

  公开（公告）日：2011-08-23
• Small, Potent, and Selective Diaryl Phosphonate Inhibitors for Urokinase-Type Plasminogen Activator with In Vivo Antimetastatic Properties
  作者：Jurgen Joossens、Omar M. Ali、Ibrahim El-Sayed、Georgiana Surpateanu、Pieter Van der Veken、Anne-Marie Lambeir、Buddy Setyono-Han、John A. Foekens、Anneliese Schneider、Wolfgang Schmalix、Achiel Haemers、Koen Augustyns

  DOI：10.1021/jm700962j

  日期：2007.12.27

  A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.