Antiplatelet efficacy and specificity of DMP728, a novel platelet GPIIb/IIIa receptor antagonist.
The present study was undertaken to define the platelet GPIIb/IIIa affinity and specificity of DMP728, the cyclic [(D-2-aminobutyrate-N-methyl-L-arginyl-glycyl-L-aspartyl)-3-aminomethyl- benzoic acid] methane sulfonate. DMP728 demonstrated similar potency (IC50 = 0.046 +/- 0.002 microM) in inhibiting human platelet aggregation induced by various agonists or combination of agonists as assessed either by light transmittance aggregometry or impedance techniques. Similarly, DMP728 inhibited (IC50 = 2.3 +/- 0.8 nM) with equipotency in inhibiting 125I-fibrinogen binding to human gel-purified platelets regardless of the agonist used. In purified human GPIIb/IIIa ELISA, DMP728 demonstrated a competitive high affinity binding (Ki = 0.4 nM). Additionally, a high binding affinity (Kd = 0.1 nM) of 3H-DMP728 was demonstrated in human platelets. Furthermore, a platelet deaggregatory efficacy was shown. DMP728 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alpha 2/beta 3) as compared to other integrins on endothelial cells (vitronectin receptors), platelets GPIb/1X, alpha v/beta 3, and other integrins on leukocytes or nonintegrin-related systems. In conclusion, DMP728 is a novel antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa.
Mousa
S A
SA
DuPont Merck Pharmaceutical Company, Cardiovascular Diseases and Biotechnology Divisions, Wilmington, DE 19880-0400.
Bozarth
J M
JM
Forsythe
M S
MS
Lorelli
W
W
Thoolen
M J
MJ
Ramachandran
N
N
Jackson
S
S
De Grado
W
W
Reilly
T M
TM
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000187:drug effects; D008698:Mesylates / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D016024:Receptors, Cytoadhesin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D019030:Receptors, Vitronectin
D016023:Integrins; D008698:Mesylates; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D016024:Receptors, Cytoadhesin; D019030:Receptors, Vitronectin; C085286:DMP 728; D005340:Fibrinogen