Thrombin active site inhibitors: chemical synthesis, in vitro and in vivo pharmacological profile of a novel and selective agent BMS-189090 and analogues

Bioorg Med Chem Lett. 2002 Jan 7;12(1):41-4. doi: 10.1016/s0960-894x(01)00664-3.

Abstract

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.

MeSH terms

  • Animals
  • Binding Sites
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical
  • Fibrinolytic Agents / chemical synthesis
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Humans
  • Mice
  • Nipecotic Acids / chemical synthesis
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology
  • Rats
  • Serine / analogs & derivatives*
  • Serine / chemical synthesis
  • Serine / chemistry
  • Serine / pharmacology
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thrombin / antagonists & inhibitors*
  • Thrombin / chemistry
  • Thrombosis / drug therapy
  • Thrombosis / prevention & control

Substances

  • BMS 189090
  • Fibrinolytic Agents
  • Nipecotic Acids
  • Serine Proteinase Inhibitors
  • Serine
  • Thrombin