Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5239-43. doi: 10.1016/j.bmcl.2013.06.028. Epub 2013 Jun 20.

Abstract

In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.

Keywords: 2-Aminoisoquinoline; Factor VIIa; Inhibition.

MeSH terms

  • Benzamidines
  • Carboxylic Acids / chemistry*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Factor VIIa / antagonists & inhibitors*
  • Factor VIIa / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzamidines
  • Carboxylic Acids
  • Serine Proteinase Inhibitors
  • Factor VIIa