Small, Low Nanomolar, Noncovalent Thrombin Inhibitors Lacking a Group to Fill the 'Distal Binding Pocket'

Bioorg Med Chem Lett. 2003 Jan 20;13(2):161-4. doi: 10.1016/s0960-894x(02)00946-0.

Abstract

Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin inhibitors which do not have a group to fill thrombin's 'distal binding pocket'. A co-crystal structure indicates the importance of an intramolecular hydrogen bond between the P1 side chain and P1/P2 amide link in this series.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacology*
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology*
  • Thrombin / antagonists & inhibitors*
  • Thrombin / chemistry

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Pyridones
  • Thrombin