Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664

Bioorg Med Chem Lett. 2002 Jan 7;12(1):45-9. doi: 10.1016/s0960-894x(01)00667-9.

Abstract

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Dipeptides / administration & dosage
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics*
  • Disease Models, Animal
  • Dogs
  • Drug Design
  • Drug Evaluation, Preclinical
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacokinetics*
  • Humans
  • Inhibitory Concentration 50
  • Macaca fascicularis
  • Mice
  • Serine Proteinase Inhibitors / administration & dosage
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Structure-Activity Relationship
  • Sulfonamides / administration & dosage
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics*
  • Thrombin / antagonists & inhibitors*
  • Thrombosis / drug therapy
  • Thrombosis / prevention & control

Substances

  • BMS 189664
  • Dipeptides
  • Fibrinolytic Agents
  • Serine Proteinase Inhibitors
  • Sulfonamides
  • Thrombin