2,3-Diamino acid modifying 3S-tetrahydroisoquinoline-3-carboxylic acids: leading to a class of novel agents with highly unfolded conformation, selective in vitro anti-platelet aggregation and potent in vivo anti-thrombotic activity

Bioorg Med Chem. 2010 Feb 15;18(4):1536-54. doi: 10.1016/j.bmc.2010.01.009. Epub 2010 Jan 13.

Abstract

In the preparation of anti-thrombotic agents the 2- and 3-positions of 3S-tetra-hydroisoquinoline-3-carboxylic acid (THIQA) were simultaneously modified with amino acids to form 20 novel N-(3S-N-aminoacyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino acids (8a-t). On an in vitro platelet aggregation model 8a-t selectively inhibit ADP-induced platelet aggregation and their IC(50) values are leas than 3.5 nM. On an extracorporeal circulation of arterioveinos cannula model of rats both orally and intraveously effective doses of 8a-t are less than 30 nmol/kg. Cerius(2) based stereoview of explores 8a-t having highly unfolded conformation. 3D QSAR analysis gives the importance of the unfolded conformation to high in vitro anti-platelet aggregation and in vivo anti-thrombotic potency rational understanding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antithrombins / chemistry*
  • Antithrombins / pharmacology
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Mass Spectrometry
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Platelet Aggregation Inhibitors / chemistry*
  • Platelet Aggregation Inhibitors / pharmacology
  • Quantitative Structure-Activity Relationship
  • Rats
  • Rats, Wistar
  • Spectrophotometry, Infrared

Substances

  • Antithrombins
  • Carboxylic Acids
  • Platelet Aggregation Inhibitors