Irreversible
platelet inhibitors, such as
aspirin and
clopidogrel, have limited anti-thrombotic efficacy in the clinic due to their
bleeding risk. We have developed an orally active reversible P2Y(12) receptor antagonist,
BX 667. The aim of this study was to determine if the reversible antagonist
BX 667 had a greater therapeutic index than the irreversible P2Y(12) receptor antagonist
clopidogrel. Since
BX 667 is rapidly converted to its active metabolite
BX 048 in rats, we first injected
BX 048 intravenously (iv) in a rat arterial venous (A-V) shunt model of
thrombosis.
BX 048 dose- and concentration-dependently attenuated
thrombosis. When administered orally,
BX 667 and
clopidogrel had similar efficacy, but
BX 667 caused less
bleeding than
clopidogrel. In a rat model of a platelet-rich
thrombus induced by vessel injury with FeCl(2), both
BX 667 and
clopidogrel exhibited higher levels of
thrombus inhibition after
oral administration compared to their potency in the A-V shunt model. Again,
BX 667 caused less
bleeding than
clopidogrel. In a dog cyclic flow model, iv injection of either
BX 667 or
clopidogrel dose-dependently reduced
thrombus formation with lower
bleeding for
BX 667 than
clopidogrel. Inhibition of
thrombosis was highly correlated with inhibition of
ADP-induced platelet aggregation in these animal models. In dogs pre-treated with
aspirin,
BX 667 maintained its wider therapeutic index, measured by inhibition of platelet aggregation over
bleeding, compared to the
aspirin-
clopidogrel combination. These data demonstrate that the reversible P2Y(12) receptor antagonist,
BX 667, has a wider therapeutic index than
clopidogrel in experimental models of
thrombosis.