Design of benzamidine-type inhibitors of factor Xa

J Med Chem. 1998 Oct 22;41(22):4240-50. doi: 10.1021/jm980227t.

Abstract

A series of derivatives of rac-benzenesulfonyl-glycyl-phenylalanine or its ethyl ester with a combination of thioamido/amidino or amidino/amidino substituents in the benzene rings was synthesized as potential inhibitors of factor Xa (fXa). Among these, the racemic 4'-amidinobenzenesulfonyl-glycyl-4-amidinophenylalanine ethyl ester was found to exhibit the highest affinity for fXa despite the unfavored location of the amidino substituent in the para position. X-ray structural analysis of the trypsin complex with this bis-benzamidine compound revealed a retro-binding mode if compared to those of similar compounds, so far analyzed in complexes with trypsin or fXa. This noncanonical binding mode as well as its slow plasma clearance rates in rats, if compared to those of other benzamidine derivatives, suggests this compound as an interesting new lead structure for the design of fXa inhibitors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamidines / chemical synthesis*
  • Benzamidines / chemistry
  • Benzamidines / pharmacokinetics
  • Benzamidines / pharmacology
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Factor Xa Inhibitors*
  • Humans
  • Hydrogen Bonding
  • Rats
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Benzamidines
  • Factor Xa Inhibitors
  • Serine Proteinase Inhibitors