Development of a novel tricyclic class of potent and selective FIXa inhibitors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5437-43. doi: 10.1016/j.bmcl.2015.07.078. Epub 2015 Jul 31.

Abstract

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Keywords: Benzimidazole; FIXa inhibitor; Quninazolinone; Structure based drug design; TGA.

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Factor IXa / antagonists & inhibitors*
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / chemistry*
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Molecular Structure
  • Rats

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Factor IXa