N-methyl-4-[4-(N-hydroxyamidino)phenoxy]thieno[2,3-c]pyridine-2-carboxamide | 251996-69-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-methyl-4-[4-(N-hydroxyamidino)phenoxy]thieno[2,3-c]pyridine-2-carboxamide
• 英文别名: 4-[4-(N'-hydroxycarbamimidoyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide
• CAS: 251996-69-7
• 化学式: C₁₆H₁₄N₄O₃S
• 分子量: 342.378
• InChiKey: BOQSTBPGWXNKDW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  138
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  三氟乙酸酐 、 N-methyl-4-[4-(N-hydroxyamidino)phenoxy]thieno[2,3-c]pyridine-2-carboxamide 在 吡啶 作用下， 反应 19.0h， 以69%的产率得到N-methyl-4-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy}thieno[2,3-c]pyridine-2-carboxamide
  参考文献：
  名称：

  Selective Inhibition of ICAM-1 and E-Selectin Expression in Human Endothelial Cells. 2. Aryl Modifications of 4-(Aryloxy)thieno[2,3-c]pyridines with Fine-Tuning at C-2 Carbamides

  摘要：

  The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counterreceptors on leukocytes, such as integrins of the alpha (L)beta (2) family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmaceutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in I with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expression. This position is presumably close to the solvent-accessible region of the target protein-inhibitor complex. An attempt to install a water-solubilizing group at the para-position of the phenoxy group to increase the aqueous solubility of this lead series through various linkages failed to provide an ideal inhibitor. Only small substituents such as fluorine are tolerated at the meta- and ortho-positions of the 4-phenoxy to retain a good in vitro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are among the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC50 < 5 nM for ICAM-1) and selective (> 200-fold vs VCAM-1) inhibitors with a good pharmacokinetic profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.

  DOI：

  10.1021/jm0101702
• 作为产物：
  描述：

  4-(4-cyanophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide 在 盐酸羟胺 、 三乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以68%的产率得到N-methyl-4-[4-(N-hydroxyamidino)phenoxy]thieno[2,3-c]pyridine-2-carboxamide
  参考文献：
  名称：

  Selective Inhibition of ICAM-1 and E-Selectin Expression in Human Endothelial Cells. 2. Aryl Modifications of 4-(Aryloxy)thieno[2,3-c]pyridines with Fine-Tuning at C-2 Carbamides

  摘要：

  The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counterreceptors on leukocytes, such as integrins of the alpha (L)beta (2) family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmaceutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in I with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expression. This position is presumably close to the solvent-accessible region of the target protein-inhibitor complex. An attempt to install a water-solubilizing group at the para-position of the phenoxy group to increase the aqueous solubility of this lead series through various linkages failed to provide an ideal inhibitor. Only small substituents such as fluorine are tolerated at the meta- and ortho-positions of the 4-phenoxy to retain a good in vitro potency. Bromo, trifluoromethyl, pyrazol-1-yl, and imidazol-1-yl are among the better substituents at the para-position. With fine-tuning at the C-2 position we discovered a series of very potent (IC50 < 5 nM for ICAM-1) and selective (> 200-fold vs VCAM-1) inhibitors with a good pharmacokinetic profile. Demonstrated efficacy in a rat rheumatoid arthritis model and in a mice asthma model with selected compounds is also reported.

  DOI：

  10.1021/jm0101702

文献信息

• Cell adhesion-inhibiting antiinflammatory compounds
  申请人：——

  公开号：US20010020030A1

  公开（公告）日：2001-09-06

  Compounds having Formula I 1 are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, and methods of inhibiting/treating inflammatory diseases in a mammal.

  具有I1式的化合物对于治疗炎症有用。本文还公开了包含I式化合物的制药组合物，以及在哺乳动物中抑制/治疗炎症性疾病的方法。
• CELL ADHESION-INHIBITING ANTIINFLAMMATORY COMPOUNDS
  申请人：ABBOTT LABORATORIES

  公开号：EP1181296A1

  公开（公告）日：2002-02-27
• US6232320B1
  申请人：——

  公开号：US6232320B1

  公开（公告）日：2001-05-15
• US6579882B2
  申请人：——

  公开号：US6579882B2

  公开（公告）日：2003-06-17
• [EN] CELL ADHESION-INHIBITING ANTIINFLAMMATORY COMPOUNDS<br/>[FR] COMPOSES ANTI-INFLAMMATOIRES INHIBANT L'ADHESION CELLULAIRE
  申请人：ABBOTT LAB

  公开号：WO2000075145A1

  公开（公告）日：2000-12-14

  Compounds having formula (I) are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of formula (I), and methods of inhibiting/treating inflammatory diseases in a mammal.