N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OMe | 190904-19-9

• 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: N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OMe
• 英文别名: methyl (2R)-3-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]propanoate
• CAS: 190904-19-9
• 化学式: C₂₁H₃₇NO₆
• 分子量: 399.528
• InChiKey: FGZPZVIAXRZIKW-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OMe 在 水 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.5h， 生成 HOCOCH2-D-Cha-Arg-NHBn(4-amidino)
  参考文献：
  名称：

  Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia

  摘要：

  A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 mu M. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.12.094
• 作为产物：
  描述：

  N-BOC-3-环己基-D-丙氨酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 N-(tert-butyloxycarbonylmethyl)-N-Boc-D-Cha-OMe
  参考文献：
  名称：

  Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety

  摘要：

  Replacement of the noragmatine group in thrombin inhibitors with a beta-alanyl-guanidine group resulted in a nearly equipotent and more selective compound 8 despite the fact that the pK(a) of this P-1 moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor with this beta-alanyl guanidine group, compound 28. This is an active and selective thrombin inhibitor and in view of its nonpeptide/low basicity structure selected for further pharmacological studies. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00650-7

文献信息

• Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics
  作者：Anton E. P. Adang、Adrianus P. A. de Man、Gerard M. T. Vogel、Peter D. J. Grootenhuis、Martin J. Smit、Co A. M. Peters、Arie Visser、Jos B. M. Rewinkel、Theo van Dinther、Hans Lucas、Jan Kelder、Sjoerd van Aelst、Dick G. Meuleman、Constant A. A. van Boeckel

  DOI：10.1021/jm011110z

  日期：2002.9.1

  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.
• Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia
  作者：Peter Bach、Laurent Knerr、Ola Fjellström、Kenny Hansson、Christer Mattsson、David Gustafsson

  DOI：10.1016/j.bmcl.2013.12.094

  日期：2014.2

  A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 mu M. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor. (C) 2014 Elsevier Ltd. All rights reserved.
• Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety
  作者：Anton E.P. Adang、Hans Lucas、Adrianus P.A. de Man、Richard A. Engh、Peter D.J. Grootenhuis

  DOI：10.1016/s0960-894x(98)00650-7

  日期：1998.12

  Replacement of the noragmatine group in thrombin inhibitors with a beta-alanyl-guanidine group resulted in a nearly equipotent and more selective compound 8 despite the fact that the pK(a) of this P-1 moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor with this beta-alanyl guanidine group, compound 28. This is an active and selective thrombin inhibitor and in view of its nonpeptide/low basicity structure selected for further pharmacological studies. (C) 1998 Elsevier Science Ltd. All rights reserved.