(S)-1-[(R)-2-(tert-Butoxycarbonyl-tert-butoxycarbonylmethyl-amino)-3-cyclohexyl-propionyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid | 203792-23-8

• 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: (S)-1-[(R)-2-(tert-Butoxycarbonyl-tert-butoxycarbonylmethyl-amino)-3-cyclohexyl-propionyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid
• CAS: 203792-23-8
• 化学式: C₂₅H₄₀N₂O₇
• 分子量: 480.602
• InChiKey: GELFMYZIYVUTMJ-RBUKOAKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.76
• 重原子数：
  34.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  113.45
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (S)-1-[(R)-2-(tert-Butoxycarbonyl-tert-butoxycarbonylmethyl-amino)-3-cyclohexyl-propionyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid 在 sodium hydroxide 、 1-羟基苯并三唑 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z
• 作为产物：
  描述：

  N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OMe 在 10percent Pd/C sodium hydroxide 、 氢气 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 (S)-1-[(R)-2-(tert-Butoxycarbonyl-tert-butoxycarbonylmethyl-amino)-3-cyclohexyl-propionyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid
  参考文献：
  名称：

  Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

  摘要：

  Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg(.)min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

  DOI：

  10.1021/jm011110z

文献信息

• d-Phe-Pro-Arg type thrombin inhibitors: unexpected selectivity by modification of the P1 moiety
  作者：Udo E.W Lange、Dorit Baucke、Wilfried Hornberger、Helmut Mack、Werner Seitz、H.Wolfgang Höffken

  DOI：10.1016/s0960-894x(03)00347-0

  日期：2003.6

  Synthesis of thrombin inhibitors and their binding mode to thrombin is described. Modification of the P1 moiety leads to an increased selectivity versus trypsin. The observed selectivity is discussed in view of their thrombin-inhibitor complex X-ray structures.
• Orally active thrombin inhibitors. Part 1: Optimization of the P1-moiety
  作者：Helmut Mack、Dorit Baucke、Wilfried Hornberger、Udo E.W. Lange、Werner Seitz、H. Wolfgang Höffken

  DOI：10.1016/j.bmcl.2006.02.040

  日期：2006.5

  The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH2-D-cyclohexylalanyl-3,.4-dehydroprolyl-NH-CH2-aryl-C(=NH)NH2 are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the D-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran. (C) 2006 Elsevier Ltd. All rights reserved.