ethyl-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate | 331005-93-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate
• 英文别名: Ethyl 2-(3-cyanophenyl)pyrazole-3-carboxylate
• CAS: 331005-93-7
• 化学式: C₁₃H₁₁N₃O₂
• 分子量: 241.249
• InChiKey: HBFDWOLJENMVBW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  67.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate 在 4-二甲氨基吡啶 、 lithium hydroxide 、 草酰氯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 2-(3-Cyano-phenyl)-2H-pyrazole-3-carboxylic acid (2'-tert-butylsulfamoyl-biphenyl-4-yl)-amide
  参考文献：
  名称：

  Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K-i = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P-1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P-4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

  DOI：

  10.1021/jm000409z
• 作为产物：
  描述：

  ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate 、 3-氰基苯肼盐酸盐 在 溶剂黄146 作用下， 反应 18.0h， 以17%的产率得到ethyl-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate
  参考文献：
  名称：

  Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K-i = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P-1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P-4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

  DOI：

  10.1021/jm000409z