Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

Bioorg Med Chem Lett. 2000 Feb 21;10(4):385-9. doi: 10.1016/s0960-894x(00)00008-1.

Abstract

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Publication types

  • Comparative Study

MeSH terms

  • Acetates / metabolism*
  • Adenosine Diphosphate / pharmacology
  • Amidines / metabolism*
  • Animals
  • Arginine / chemistry
  • Benzamidines / chemistry
  • Biological Availability
  • Drug Evaluation
  • Enzyme-Linked Immunosorbent Assay
  • Fibrinogen / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Platelet Aggregation / drug effects
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Rats
  • Stereoisomerism
  • Tetralones*

Substances

  • 6-((4-amidinobenzoyl)amino)tetralone-2-acetic acid
  • Acetates
  • Amidines
  • Benzamidines
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Prodrugs
  • Tetralones
  • Adenosine Diphosphate
  • Fibrinogen
  • Arginine
  • benzamidine