Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp

• Published in: Journal of medicinal chemistry 1994-08, Vol.37 (16), p.2537-2551
• Main Authors: Egbertson, Melissa S, Chang, Charles T.-C, Duggan, Mark E, Gould, Robert J, Halczenko, Wasyl, Hartman, George D, Laswell, William L, Lynch, Joseph J, Lynch, Robert J
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - pharmacology; Amino Acid Sequence; Animals; Dogs; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Humans; Kinetics; Models, Molecular; Molecular Sequence Data; Molecular Structure; Oligopeptides - pharmacology; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Platelet Membrane Glycoproteins - antagonists & inhibitors; Structure-Activity Relationship; Templates, Genetic; Tirofiban; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - pharmacology; Umbilical Veins
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00042a007

Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation. Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of > 24,000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with i.v. infusions of 0.1-10 micrograms/kg/min of 23m in anesthetized dogs, with 10 micrograms/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infusions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.