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

Abstract

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.

Species differences in small molecule binding to αIIbβ3 are the result of sequence differences in 2 loops of the αIIb β propeller

“…[34][35][36] Like RGDS, echistatin and eristostatin, tirofiban and eptifibatide have little effect on rat platelets. Thus, although 10 nM tirofiban reduced DTT-induced fibrinogen binding to human ␣IIb␤3 on CHO cells by 82.2% plus or minus 1.5%, it reduced fibrinogen binding to rat ␣IIb by only 22.2% plus or minus 2.4% ( Figure 5A).…”

Self-assembled nanoparticles based on the c(RGDfk) peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

“…4 Additionally, these carriers have been modified with different targeting ligands, such as the Arg-Glytargeting ability. The RGD peptide and structurally related compounds [9][10][11][12][13][14] are the best-studied ligands that belong to the integrin ligand group. [15][16][17][18] Because these ligands specifically bind to the integrin receptor, which is overexpressed in the endothelial cells of the tumor neovasculature, 19 when applied in vivo, an 8-amino-3,6-dioxaoctanoic acid (PEG)-β-maleimidopropionic acid (MAL) hydrophilically modified, specific integrin αvβ3 receptor-targeted small cyclopeptide c(RGDfk) could lead to the accumulation of siRNA in tumors, resulting in tumor targeting.…”

Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

“…[16][17][18][19] The most studied integrin ligands have been the Arg-Gly-Asp (RGD) motif and structurally related compounds. [20][21][22][23][24][25] The RGD motif can be specifically recognized by integrins α ν β 3 and α ν β 5 which are overexpressed on many solid tumors and in tumor neovasculature, such as in human glioma. 26 Thus, modification of SSL with the RGD motif to achieve targeted drug delivery to tumors and the tumor neovasculature is a promising strategy in the treatment of glioma.…”