Design and synthesis of conformationally restricted inhibitors of active thrombin activatable fibrinolysis inhibitor (TAFIa)

Bioorg Med Chem. 2014 Apr 1;22(7):2261-8. doi: 10.1016/j.bmc.2014.02.010. Epub 2014 Feb 18.

Abstract

A series of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid derivatives designed as inhibitors of TAFIa has been prepared via a common hydrogenation-alkylation sequence starting from the appropriate benzimidazole and imidazopyridine system. We present a successful design strategy using a conformational restriction approach resulting in potent and selective inhibitors of TAFIa. The X-ray structure of compound 5 in complex with a H333Y/H335Q double mutant TAFI indicate that the conformational restriction is responsible for the observed potency increase.

Keywords: AstraZeneca; Carboxypeptidase U; Conformational restriction; Imidazole; Rigidification; TAFIa.

MeSH terms

  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Caco-2 Cells
  • Carboxypeptidase B2 / antagonists & inhibitors*
  • Carboxypeptidase B2 / genetics
  • Carboxypeptidase B2 / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Enzyme Inhibitors
  • Pyridines
  • Carboxypeptidase B2