Novel nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist, DMP754: receptor binding affinity and specificity.
OBJECTIVE
To define the antiplatelet efficacy and specificity of the glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist prodrug DMP754 and its free acid form, XV459.


METHODS
DMP754 has an IC50 > 1 mumol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting human platelet aggregation induced by 10 mumol/l adenosine diphosphate, 20 micrograms/ml collagen, 1 mmol/l epinephrine, 10 mumol/l platelet activating factor or 0.5 IU/ml thrombin. The in-vitro rate of hydrolysis of DMP754 or XV459 is much faster with human or canine liver esterases (t 1/2 = 2.4-23 min) than with plasma esterases (t 1/2 = 5.5-7.6 h). Platelet GpIIb/IIIa integrin binding affinity and specificity for XV459 were determined using cell binding/adhesion assays.


RESULTS
The range of IC50 values of XV459 in inhibiting platelet aggregation in platelet-rich plasma obtained from 12 subjects was 0.035-0.069 mumol/l with a mean IC50 of 0.050 +/- 0.003 mumol/l. Additionally, XV459 inhibited platelets obtained from mongrel dogs, baboons, sheep, guinea pigs, and mice with IC50 in the range 0.024-0.06 mumol/l, and IC50 in the range 0.16-5.8 mumol/l in pigs, rabbits, and rats. XV459 inhibited [125I]-fibrinogen binding to activated human platelets with an IC50 of 0.011 +/- 0.003 mumol/l. XV459 demonstrated a high degree of selectivity in specifically inhibiting fibrinogen binding to the platelet integrin, GPIIb/IIIa (IC50 = 0.00025 +/- 0.00005 mumol/l) compared with inhibiting other integrins (alpha v beta 3, IC50 > 10 mumol/l; or alpha v beta 5, alpha 5 beta 1, or alpha 4 beta 1, for which the IC50 exceeded 100 mumol/l).


CONCLUSIONS
DMP754 is a potent antiplatelet agent in inhibiting platelet aggregation, and has a high specificity and affinity for human platelet GPIIb/IIIa receptors.
Mousa
S A
SA
DuPont Merck Pharmaceutical Co., Wilmington, Delaware, USA.
Forsythe
M
M
Lorelli
W
W
Bozarth
J
J
Xue
C B
CB
Wityak
J
J
Sielecki
T M
TM
Olson
R E
RE
DeGrado
W
W
Kapil
R
R
Hussain
M
M
Wexler
R
R
Thoolen
M J
MJ
Reilly
T M
TM
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion; D004285:Dogs; D005340:Fibrinogen / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D016023:Integrins / Q000502:physiology; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012680:Sensitivity and Specificity; D013045:Species Specificity
D000596:Amino Acids; D016023:Integrins; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104284:XV 459; C104283:roxifiban acetate; D005340:Fibrinogen