Design, synthesis and biological activity of novel rigid amidino-phenylalanine derivatives as inhibitors of thrombin

J Enzyme Inhib. 1995;9(1):73-86. doi: 10.3109/14756369509040682.

Abstract

(3S)-(Naphthalene-2-sulfonylamino)-1-[2R-(4-amidinophenyl)-1- piperidinocarbonylethyl]-2-pyrrolidinone (1a) is a potent inhibitor of thrombin with an IC50 value by 112 times lower than that of NAPAP (racemate). The selectivity versus trypsin can be improved by incorporation of substituents on the naphthyl ring. The mode of binding of the compound was determined by X-ray crystallography.

MeSH terms

  • Animals
  • Antithrombins / chemical synthesis
  • Antithrombins / chemistry
  • Antithrombins / metabolism
  • Antithrombins / pharmacology*
  • Benzamidines / chemical synthesis
  • Benzamidines / chemistry
  • Benzamidines / pharmacology*
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Dipeptides / chemistry
  • Dipeptides / metabolism
  • Dipeptides / pharmacology
  • Drug Design
  • Hydrogen Bonding
  • Lactams / chemical synthesis
  • Lactams / pharmacology
  • Molecular Structure
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacology*
  • Rats
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Trypsin / metabolism

Substances

  • 3-(naphthalene-2-sulfonylamino)-1-(2-(4-amidinophenyl)-1-piperidinocarbonylethyl)-2-pyrrolidinone
  • Antithrombins
  • Benzamidines
  • Dipeptides
  • Lactams
  • Piperidines
  • Pyrrolidinones
  • Serine Proteinase Inhibitors
  • N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide
  • Trypsin
  • Thrombin