Structural modification of an orally active thrombin inhibitor, LB30057: replacement of the D-pocket-binding naphthyl moiety

Bioorg Med Chem. 1998 Jun;6(6):869-76. doi: 10.1016/s0968-0896(98)00044-3.

Abstract

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (Ki = 0.38 nM), selective, and orally active thrombin inhibitor. As a continuation of studies into benzamidrazone-based thrombin inhibitors, we have structurally modified compound 2 by replacing the naphthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin and oral absorption. The highest activity was obtained with compound 23 (Ki = 0.045 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Cattle
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Models, Molecular
  • Rats
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*
  • Trypsin Inhibitors / chemical synthesis
  • Trypsin Inhibitors / chemistry
  • Trypsin Inhibitors / pharmacokinetics
  • Trypsin Inhibitors / pharmacology

Substances

  • Enzyme Inhibitors
  • Trypsin Inhibitors
  • Thrombin