1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(hydroxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(hydroxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole
• 英文别名: 2-[[2-[2-(4-carbamimidoylphenyl)ethyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetic acid
• 化学式: C₂₈H₂₆N₆O₄S
• 分子量: 542.618
• InChiKey: AUMKTQJOSFGRPC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  164
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-氰基-3-苯基丙酸 在 10percent Pd/C 吡啶 、 盐酸 、 sodium hydroxide 、 氢气 、 potassium carbonate 、 溶剂黄146 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 丙酮 为溶剂， 生成 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(hydroxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole
  参考文献：
  名称：

  Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors

  摘要：

  The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.

  DOI：

  10.1021/jm0109513

文献信息

• US6121308
  申请人：——

  公开号：——

  公开（公告）日：——
• US06121308
  申请人：——

  公开号：——

  公开（公告）日：——
• DISUBSTITUIERTE BICYCLISCHE HETEROCYCLEN MIT INSBESONDERE EINE THROMBINHEMMENDE WIRKUNG
  申请人：Boehringer Ingelheim Pharma GmbH & Co.KG

  公开号：EP1100795B1

  公开（公告）日：2004-06-09
• US6121308A
  申请人：——

  公开号：US6121308A

  公开（公告）日：2000-09-19
• Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors
  作者：Norbert H. Hauel、Herbert Nar、Henning Priepke、Uwe Ries、Jean-Marie Stassen、Wolfgang Wienen

  DOI：10.1021/jm0109513

  日期：2002.4.1

  The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.