biphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide | 186550-30-1

• 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: biphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide
• 英文别名: N-[(3S)-1-[(3-cyanophenyl)methyl]-2-oxopyrrolidin-3-yl]-4-phenylbenzenesulfonamide
• CAS: 186550-30-1
• 化学式: C₂₄H₂₁N₃O₃S
• 分子量: 431.515
• InChiKey: DQCTULKVFJUBNA-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  98.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  biphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成
  参考文献：
  名称：

  Design and Structure−Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

  摘要：

  The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (Ki = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl2-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.

  DOI：

  10.1021/jm990040h
• 作为产物：
  描述：

  [1-(3-cyanobenzyl)-2-oxopyrrolidin-3(S)-yl]carbamic acid tert-butyl ester 在 盐酸 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 6.0h， 生成 biphenyl-4-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide
  参考文献：
  名称：

  Design and Structure−Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

  摘要：

  The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (Ki = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl2-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.

  DOI：

  10.1021/jm990040h

文献信息

• Sulfonamidopyrrolidinone Factor Xa Inhibitors:  Potency and Selectivity Enhancements via P-1 and P-4 Optimization
  作者：Yong Mi Choi-Sledeski、Daniel G. McGarry、Daniel M. Green、Helen J. Mason、Michael R. Becker、Roderick S. Davis、William R. Ewing、William P. Dankulich、Vincent E. Manetta、Robert L. Morris、Alfred P. Spada、Daniel L. Cheney、Karen D. Brown、Dennis J. Colussi、Valeria Chu、Christopher L. Heran、Suzanne R. Morgan、Ross G. Bentley、Robert J. Leadley、Sebastien Maignan、Jean-Pierre Guilloteau、Christopher T. Dunwiddie、Henry W. Pauls

  DOI：10.1021/jm990041+

  日期：1999.9.1

  4-aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination

  磺酰胺基吡咯烷酮是先前公开的选择性类别的因子Xa（fXa）抑制剂，最终鉴定为RPR120844作为体内有效成员。认识到中央吡咯烷酮模板可用于将配体呈递给fXa的S-1和S-4亚基，因此开始了优化P-1和P-4组的研究。发现含有4-羟基-和4-氨基苯甲m的磺酰胺基吡咯烷酮是fXa的有效抑制剂。胰蛋白酶和分子模型研究中的X射线晶体学实验表明，我们的抑制剂通过将4-羟基苯甲m部分插入fXa活性位点的S-1子位而结合。在所审查的P-4组中，发现吡啶基噻吩基磺酰胺具有优异的效价和选择性，特别是与4-羟基苯甲m联用时。化合物20b（RPR130737）被证明是有效的fXa抑制剂（K（i）= 2 nM），对结构相关的丝氨酸蛋白酶具有选择性（> 1000倍）。初步生物学评估证明了该抑制剂在体外（例如活化的部分凝血活酶时间）和体内（例如大鼠FeCl（2）诱导的颈动脉血栓形成模型）血栓形成的常见测定中的有效性。
• SUBSTITUTED (SULFINIC ACID, SULFONIC ACID, SULFONYLAMINO OR SULFINYLAMINO) N- (AMINOIMINOMETHYL)PHENYLALKYL -AZAHETEROCYCLYLAMIDE COMPOUNDS
  申请人：Aventis Pharmaceuticals Inc.

  公开号：EP0853618B1

  公开（公告）日：2011-08-17
• US5958918A
  申请人：——

  公开号：US5958918A

  公开（公告）日：1999-09-28
• Design and Structure−Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa
  作者：William R. Ewing、Michael R. Becker、Vincent E. Manetta、Roderick S. Davis、Henry W. Pauls、Helen Mason、Yong Mi Choi-Sledeski、Daniel Green、Don Cha、Alfred P. Spada、Daniel L. Cheney、Jonathan S. Mason、Sebastien Maignan、Jean-Pierre Guilloteau、Karen Brown、Dennis Colussi、Ross Bentley、Jeff Bostwick、Charles J. Kasiewski、Suzanne R. Morgan、Robert J. Leadley、Christopher T. Dunwiddie、Mark H. Perrone、Valeria Chu

  DOI：10.1021/jm990040h

  日期：1999.9.1

  The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (Ki = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl2-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.