Oral antiplatelet efficacy and specificity of a novel nonpeptide platelet GPIIb/IIIa receptor antagonist, DMP 802.
This study was undertaken to define the platelet glycoprotein alphaIIb beta3 integrin (GPII/IIIa) affinity, specificity, and oral antiplatelet efficacy of DMP 802, a small-molecule nonpeptide antiplatelet agent. Platelet GPIIb/IIIa integrin binding affinity and specificity for DMP 802 were determined by using binding and adhesion assays with cells from various species, including human. DMP 802 demonstrated a potent antiplatelet efficacy [median inhibitory concentration (IC50), 0.029 +/- 0.0042 microM] in inhibiting human platelet aggregation induced by 10 microM adenosine diphosphate (ADP), as assessed by light-transmittance aggregometry. DMP 802 inhibited 125I-fibrinogen binding to activated (ADP, epinephrine, and arachidonic acid at 100 microM each) gel purified human platelets with an IC50 of 0.012 +/- 0.003 microM. DMP 802 demonstrated tight association with unactivated human, baboon, or canine platelets (t(1/2) of dissociation, 32 +/- 2, 32 +/- 13, and 11 +/- 1 min, respectively). DMP 802 binds with high affinity to both unactivated and activated human platelets (Kd = 0.61 +/- 0.17, 0.57 +/- 0.21 nM, respectively). DMP 802 demonstrated species specificity in inhibiting platelet aggregation with IC50 values ranging from 0.025 to 0.092 microM (human, guinea pig, dog, swine, hamster) and 0.88-1.0 microM (rabbit and rat) in platelets obtained from these various species. DMP 802 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb/beta3) as compared with other integrins including alpha(v)beta3 (IC50, >10 microM), alpha(v)beta5 (IC50, >100 microM), alpha4beta1 (IC50, >100 microM), and alpha5beta1 (IC50, >10 microM). Oral antiplatelet efficacy of DMP 802 was examined after single oral (0.05-0.20 mg/kg) and after repeated oral dosing at 0.05 mg/kg daily for 5 days in mongrel dogs. Dose-dependent antiplatelet efficacy with an extended duration of antiplatelet efficacy was demonstrated based on ex vivo inhibition of platelet aggregation induced by 100 microM ADP. DMP 802 has an oral bioavailability of 14.9% in dogs. In conclusion, the alpha sulfonamide isoxazoline analog, DMP 802, is a novel oral antiplatelet agent with high affinity, relatively slow dissociation rate and specificity for human platelet GPIIb/IIIa receptors.
The DuPont Merck Pharmaceutical Co., Wilmington, Delaware 19880-0400, USA.
S A
SA
Mousa
R E
RE
Olson
J M
JM
Bozarth
W
W
Lorelli
M S
MS
Forsythe
A
A
Racanelli
S
S
Gibbs
K
K
Schlingman
T
T
Bozarth
R
R
Kapil
J
J
Wityak
T M
TM
Sielecki
R R
RR
Wexler
M J
MJ
Thoolen
A
A
Slee
T M
TM
Reilly
P S
PS
Anderson
P A
PA
Friedman
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D019096:Vitronectin / Q000378:metabolism
C114713:DMP 802; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016201:Receptors, Lymphocyte Homing; D019030:Receptors, Vitronectin; D013449:Sulfonamides; D019096:Vitronectin