N-fluorenylmethoxycarbonyl-L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide | 439117-43-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: N-fluorenylmethoxycarbonyl-L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide
• 英文别名: 9H-fluoren-9-ylmethyl (2S)-2-[[5-chloro-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate
• CAS: 439117-43-8
• 化学式: C₃₃H₃₆ClN₃O₅
• 分子量: 590.119
• InChiKey: XDHZWKXJWXJYQT-LJAQVGFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  97
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-fluorenylmethoxycarbonyl-L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide 在 哌啶 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-((2R)-Hydroxy-3-methylbutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide
  参考文献：
  名称：

  Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability

  摘要：

  Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.06.030
• 作为产物：
  描述：

  1-azidomethyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzene 在 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-fluorenylmethoxycarbonyl-L-prolyl-2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzylamide
  参考文献：
  名称：

  Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability

  摘要：

  Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.06.030

文献信息

• Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement
  作者：Harry R. Chobanian、Barbara Pio、Yan Guo、Hong Shen、Mark A. Huffman、Maria Madeira、Gino Salituro、Jenna L. Terebetski、James Ormes、Nina Jochnowitz、Lizbeth Hoos、Yuchen Zhou、Dale Lewis、Brian Hawes、Lyndon Mitnaul、Kim O’Neill、Kenneth Ellsworth、Liangsu Wang、Tesfaye Biftu、Joseph L. Duffy

  DOI：10.1021/acsmedchemlett.5b00047

  日期：2015.5.14

  Modification of the previously disclosed (S)-N-(2-aminmethyl-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.
• 9-Hydroxyazafluorenes and Their Use in Thrombin Inhibitors
  作者：Kenneth J. Stauffer、Peter D. Williams、Harold G. Selnick、Philippe G. Nantermet、Christina L. Newton、Carl F. Homnick、Matthew M. Zrada、S. Dale Lewis、Bobby J. Lucas、Julie A. Krueger、Beth L. Pietrak、Elizabeth A. Lyle、Rominder Singh、Cynthia Miller-Stein、Rebecca B. White、Bradley Wong、Audrey A. Wallace、Gary R. Sitko、Jacquelyn J. Cook、Marie A. Holahan、Maria Stranieri-Michener、Yvonne M. Leonard、Joseph J. Lynch,、Daniel R. McMasters、Youwei Yan

  DOI：10.1021/jm049423s

  日期：2005.4.1

  Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.