2-(3-cyanophenyl)-N-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide | 209960-87-2

• 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: 2-(3-cyanophenyl)-N-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
• CAS: 209960-87-2
• 化学式: C₂₅H₁₆F₄N₄O₃S
• 分子量: 528.487
• InChiKey: HDGGDIVULHQOLF-UHFFFAOYSA-N

物化性质

• 沸点：
  633.5±55.0 °C(Predicted)
• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-(3-cyanophenyl)-N-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide 在 氢气 、 钯 、 三氟乙酸 作用下， 以 甲醇 为溶剂， 以80%的产率得到1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
  参考文献：
  名称：

  共激活因子相关的精氨酸甲基转移酶1（CARM1）的吡唑抑制剂。

  摘要：

  这项研究报告了共激活因子相关的精氨酸甲基转移酶（CARM1）抑制剂的鉴定和最优化线索。化合物7b是有效的，选择性的CARM1抑制剂。

  DOI：

  10.1016/j.bmcl.2008.06.026
• 作为产物：
  描述：

  1-(3-氰基苯基)-5-羟甲基-3-三氟甲基吡唑 在 4-二甲氨基吡啶 、 ruthenium trichloride 、 sodium periodate 、 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 20.0h， 生成 2-(3-cyanophenyl)-N-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
  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

文献信息

• NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP0946508B1

  公开（公告）日：2009-09-23
• Phenyltriazolinones as potent factor Xa inhibitors
  作者：Mimi L. Quan、Donald J.P. Pinto、Karen A. Rossi、Steven Sheriff、Richard S. Alexander、Eugene Amparo、Kevin Kish、Robert M. Knabb、Joseph M. Luettgen、Paul Morin、Angela Smallwood、Francis J. Woerner、Ruth R. Wexler

  DOI：10.1016/j.bmcl.2010.01.011

  日期：2010.2

  We have discovered that phenyltriazolinone is a novel and potent P-1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P-1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S-1 binding pocket which is larger in size to accommodate the phenyltriazolinone P-1 substrate. (C) 2010 Elsevier Ltd. All rights reserved.
• Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1)
  作者：Ashok V. Purandare、Zhong Chen、Tram Huynh、Suhong Pang、Jieping Geng、Wayne Vaccaro、Michael A. Poss、Jonathan Oconnell、Kimberly Nowak、Lata Jayaraman

  DOI：10.1016/j.bmcl.2008.06.026

  日期：2008.8

  This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.

  这项研究报告了共激活因子相关的精氨酸甲基转移酶（CARM1）抑制剂的鉴定和最优化线索。化合物7b是有效的，选择性的CARM1抑制剂。
• Discovery of 1-[3-(Aminomethyl)phenyl]-<i>N</i>-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1<i>H</i>-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa
  作者：Donald J. P. Pinto、Michael J. Orwat、Shuaige Wang、John M. Fevig、Mimi L. Quan、Eugene Amparo、Joseph Cacciola、Karen A. Rossi、Richard S. Alexander、Angela M. Smallwood、Joseph M. Luettgen、Li Liang、Bruce J. Aungst、Matthew R. Wright、Robert M. Knabb、Pancras C. Wong、Ruth R. Wexler、Patrick Y. S. Lam

  DOI：10.1021/jm000409z

  日期：2001.2.1

  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.