Cyclic deriv. 36 | 777840-91-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: Cyclic deriv. 36
• 英文别名: 2-[4-chloro-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]sulfonylisoquinolin-1-yl]guanidine
• CAS: 777840-91-2
• 化学式: C₁₅H₁₈ClN₅O₃S
• 分子量: 383.859
• InChiKey: OQMRNIRRUCXMGT-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  143
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Cyclic deriv. 36 在 草酰氯 、 N,N-二甲基甲酰胺 、 氨 作用下， 以 二氯甲烷 为溶剂， 反应 18.17h， 以102 mg的产率得到(2R)-1-({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)-2-pyrrolidinecarboxamide
  参考文献：
  名称：

  Selective Urokinase-Type Plasminogen Activator Inhibitors. 4. 1-(7-Sulfonamidoisoquinolinyl)guanidines

  摘要：

  1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.

  DOI：

  10.1021/jm061066t
• 作为产物：
  描述：

  D-脯氨醇 在 sodium hydride 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 31.33h， 生成 Cyclic deriv. 36
  参考文献：
  名称：

  Selective Urokinase-Type Plasminogen Activator Inhibitors. 4. 1-(7-Sulfonamidoisoquinolinyl)guanidines

  摘要：

  1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.

  DOI：

  10.1021/jm061066t

文献信息

• ISOQUINOLINES AS UROKINASE INHIBITORS
  申请人：PFIZER INC.

  公开号：EP1077945B1

  公开（公告）日：2003-01-08