Selective and dual action orally active inhibitors of thrombin and factor Xa

Bioorg Med Chem Lett. 2007 May 15;17(10):2927-30. doi: 10.1016/j.bmcl.2007.03.080. Epub 2007 Mar 30.

Abstract

The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

MeSH terms

  • Animals
  • Dogs
  • Factor Xa Inhibitors*
  • Fibrinolytic Agents / chemical synthesis
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*
  • Thrombin / antagonists & inhibitors*

Substances

  • 2-(5-chlorothien-2-yl)-N-((3S)-1-((1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide
  • Factor Xa Inhibitors
  • Fibrinolytic Agents
  • Morpholines
  • Sulfonamides
  • Thrombin