Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor

Bioorg Med Chem Lett. 2010 Jan 1;20(1):92-6. doi: 10.1016/j.bmcl.2009.11.029. Epub 2009 Nov 13.

Abstract

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.

MeSH terms

  • Administration, Oral
  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Amino Acids / pharmacokinetics
  • Animals
  • Carboxypeptidase B2 / antagonists & inhibitors*
  • Carboxypeptidase B2 / metabolism
  • Fibrinolytic Agents / chemical synthesis
  • Fibrinolytic Agents / chemistry*
  • Fibrinolytic Agents / pharmacokinetics
  • Half-Life
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Oxygen / chemistry*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Rats
  • Structure-Activity Relationship

Substances

  • 5-amino-2-((1-n-propyl-1H-imidazol-4-yl)methyl)pentanoic acid
  • Amino Acids
  • Fibrinolytic Agents
  • Imidazoles
  • Protease Inhibitors
  • Carboxypeptidase B2
  • Oxygen