Heterocyclic core analogs of a direct thrombin inhibitor

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1111-5. doi: 10.1016/j.bmcl.2014.01.002. Epub 2014 Jan 10.


Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.

Keywords: Anti-thrombotic; DTI; Thrombin inhibitor; Thrombosis.

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism


  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Thrombin