benzyl ((4-carbamimidoylphenyl)(diphenoxyphosphoryl)methyl)carbamate | 153889-36-2

• 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 ((4-carbamimidoylphenyl)(diphenoxyphosphoryl)methyl)carbamate
• 英文别名: [N-(benzyloxycarbonyl)amino](4-amidinophenyl)methane phosphonate；Diphenyl N-(benzyloxycarbonyl)amino(4-amidinophenyl)methanephosphonate；Diphenyl 1-(N-benzyloxycarbonylamino)-1-(4-amidinophenyl)methanephosphonate；benzyl N-[(4-carbamimidoylphenyl)-diphenoxyphosphorylmethyl]carbamate
• CAS: 153889-36-2
• 化学式: C₂₈H₂₆N₃O₅P
• 分子量: 515.505
• InChiKey: WYCVSPRVSFUVMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  benzyl ((4-carbamimidoylphenyl)(diphenoxyphosphoryl)methyl)carbamate 在 盐酸 、 TEA 、 氢气 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 Diphenyl N-(trans-Cinnamoyl)amino(4-amidinophenyl)methanephosphonate Hydrochloride
  参考文献：
  名称：

  Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

  摘要：

  Thirty-six new amino acid and peptidyl diphenyl phosphonate esters were synthesized and evaluated to identify potent and selective inhibitors for four trypsin-like proteases: lymphocyte granzymes A and K, human mast cell tryptase, and pancreatic trypsin. Among five Cbz derivatives of Lys and Arg homologues, Z-(4-AmPhe)(P)(OPh)(2) is the mast potent inhibitor for granzyme A, and Z-Lys(P)(OPh)(2) is the best inhibitor for granzyme K, mast tryptase, and trypsin. The amidino P1 residue D,L-(4-AmPhGly)(P)(OPh)(2) was utilized in a series of compounds with several different N-protecting groups and systematic substitutions at P2 in Cbz-AA derivatives and at P3 in Cbz-AA-Ala derivatives. Generally, these phosphonates inhibit granzyme A and trypsin more potently than granzyme K and tryptase. The P2 Thr and Ala dipeptide phosphonates, Cbz-AA-(4-AmPhGly)(P)(OPh)(2), are the most potent inhibitors for granzyme A, and Cbz-Thr-(4-AmPhGly)(P)(OPh)(2) (k(obs)/[I] = 2220 M-1 s(-1)) was quite specific with much lower inhibition rates for granzyme K and trypsin (k(obs)/[I] = 3 and 97 M-1 s(-1), respectively) and no inhibition with tryptase. The most effective inhibitor of granzyme A was Ph-SO2-Gly-Pro-(4-AmPhGly)(P)(OPh)(2) with a second-order rate constant of 3650 M-1 s(-1). The most potent inhibitor for granzyme K was 3,3-diphenylpropanoyl-Pro-(4-AmPhGly)(P)(OPh)(2) with a k(obs)/[I] = 1830 M-1 s(-1) all other phosphonates inhibited granzyme K weakly (k(obs)[I] < 60 M-1 s(-1)). Human mast cell tryptase was inhibited slowly by these phosphonates with Cbz-Lys(P)(OPh)(2) as the best inhibitor (k(obs)/[I] = 89 M-1 s(-1)). The overall results suggest that scaffolds of Phe-Thr-(4-AmPhe) and Phe-Pro-Lys will be useful to create selective phosphonate inhibitors for granzymes A and K, respectively, and that P4 substituents offer opportunities to further enhance selectivity and reactivity.

  DOI：

  10.1021/jm970543s
• 作为产物：
  描述：

  diphenyl [N-(benzyloxycarbonyl)amino(4-cyanophenyl)methyl]phosphonate 在 溶剂黄146 、 锌 作用下， 以 乙醇 、 乙腈 为溶剂， 生成 benzyl ((4-carbamimidoylphenyl)(diphenoxyphosphoryl)methyl)carbamate
  参考文献：
  名称：

  The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics

  摘要：

  我们报告了第一批高效、选择性的小分子KLK4抑制剂，显示出令人惊讶的可逆结合动力学。

  DOI：

  10.1039/c5md00288e

文献信息

• Covalently reactive transition state analogs and methods of use thereof
  申请人：Paul Sudhir

  公开号：US20050142649A1

  公开（公告）日：2005-06-30

  Improved methods for the production, selection and inhibition of catalytic antibodies are disclosed.

  本发明揭示了用于生产、选择和抑制催化抗体的改进方法。
• Proteolytic and covalent antibodies
  申请人：Paul Sudhir

  公开号：US20070105092A1

  公开（公告）日：2007-05-10

  Improved methods for the production, selection and inhibition of catalytic and covalent antibodies are disclosed.

  本发明公开了生产、选择和抑制催化性和共价抗体的改进方法。
• Covalent attachment of ligands to nucleophilic proteins guided by non-covalent binding
  申请人：Paul Sudhir

  公开号：US20070179083A1

  公开（公告）日：2007-08-02

  A covalently reactive ligand analogue (CAL) of formula (1): wherein, L 1 . . . L x . . . L m are components defining a ligand determinant, L x is a component unit of the ligand determinant selected from the group consisting of an amino acid residue, sugar residue, a fatty acid residue and a nucleotide, L′ is a functional group of L x , Y″ is atom, covalent bond or linker, Y′ is an optional charged or neutral group Y is a covalently reactive electrophilic group that reacts specifically with a receptor that binds to said ligand determinant, and n is an integer from 1 to 1000 m is an integer from 1 to 30.

  一种共价反应配体类似物(CAL)，其化学式为(1)：其中，L1...Lx...Lm是定义配体决定因子的组成部分，Lx是从氨基酸残基、糖残基、脂肪酸残基和核苷酸组成的配体决定因子的组分单元，L'是Lx的功能基团，Y"是原子、共价键或连接剂，Y'是可选的带电或中性基团，Y是共价反应电子亲和性基团，其特异地反应于与所述配体决定因子结合的受体，n是1至1000的整数，m是1至30的整数。
• Synthesis and kinetic studies of an amidine-containing phosphonofluoridate: a novel potent inhibitor of trypsin-like enzymes
  作者：Li-Ming Ni、James C. Powers

  DOI：10.1016/s0968-0896(98)00109-6

  日期：1998.10

  also inactivates trypsin 2 orders of magnitude more potently than simple phosphonofluoridates such as DFP,1 Sarin and Soman. The phosphonofluoridate 3 does not inhibit other serine proteases such as porcine pancreatic elastase (PPE) and the esterase acetylcholinesterase (AChE). The phosphonofluoridate 3 is hydrolyzed rapidly in buffer solution and has a t1/2 of 4.5 s at pH 7.5.

  含am的α-氨基烷基膦酰氟3（Cbz-（4-AmPhGly）P（OPh）（F））是一种非常有效的胰蛋白酶样酶抑制剂。它是通过水解相应的膦酸酯二苯酯4，然后使氟化物与由中间体膦酸单酯5制备的膦酰氯反应而制得的。化合物3是迄今报道的胰蛋白酶样酶中最有效的含am有机磷抑制剂。它以2.6 x 10（5）M-1 s-1和1.0 x 10（5）M-1 s-1的二级速率常数（Kobs / [I]）抑制胰蛋白酶和凝血酶，显示出130和相应的二苯酯（4）的合成速率提高了12倍和1250倍。它也比简单的磷酸膦酰氟（如DFP，1 Sarin和Soman）更有效地灭活胰蛋白酶2个数量级。膦酰氟3不会抑制其他丝氨酸蛋白酶，例如猪胰弹性蛋白酶（PPE）和酯酶乙酰胆碱酯酶（AChE）。氟膦酸膦酸酯3在缓冲溶液中迅速水解，在pH 7.5下的t1 / 2为4.5 s。
• Synthesis and Structure–Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from <i>Plasmodium falciparum</i>
  作者：Komagal Kannan Sivaraman、Alessandro Paiardini、Marcin Sieńczyk、Chiara Ruggeri、Christine A. Oellig、John P. Dalton、Peter J. Scammells、Marcin Drag、Sheena McGowan

  DOI：10.1021/jm4005972

  日期：2013.6.27

  The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the SI pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.