A novel P2Y12 adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models

Yi-Xin Wang; Jon Vincelette; Valdeci da Cunha; Baby Martin-McNulty; Cornell Mallari; Richard M. Fitch; Serene Alexander; Imadul Islam; Brad O. Buckman; Shendong Yuan; Joseph M. Post; Babu Subramanyam; Ronald Vergona; Mark E. Sullivan; William P. Dole; John Morser; Judi Bryant

doi:10.1160/TH06-12-0732

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(05): 847-855
DOI: 10.1160/TH06-12-0732

Animal Models

Schattauer GmbH

A novel P2Y₁₂ adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models

Yi-Xin Wang

¹Berlex Biosciences, Richmond, California, USA

,

Jon Vincelette

¹Berlex Biosciences, Richmond, California, USA

,

Valdeci da Cunha

¹Berlex Biosciences, Richmond, California, USA

,

Baby Martin-McNulty

¹Berlex Biosciences, Richmond, California, USA

,

Cornell Mallari

¹Berlex Biosciences, Richmond, California, USA

,

Richard M. Fitch

¹Berlex Biosciences, Richmond, California, USA

,

Serene Alexander

¹Berlex Biosciences, Richmond, California, USA

,

Imadul Islam

¹Berlex Biosciences, Richmond, California, USA

,

Brad O. Buckman

¹Berlex Biosciences, Richmond, California, USA

,

Shendong Yuan

¹Berlex Biosciences, Richmond, California, USA

,

Joseph M. Post

¹Berlex Biosciences, Richmond, California, USA

,

Babu Subramanyam

¹Berlex Biosciences, Richmond, California, USA

,

Ronald Vergona

¹Berlex Biosciences, Richmond, California, USA

,

Mark E. Sullivan

¹Berlex Biosciences, Richmond, California, USA

,

William P. Dole

¹Berlex Biosciences, Richmond, California, USA

,

John Morser

¹Berlex Biosciences, Richmond, California, USA

,

Judi Bryant

¹Berlex Biosciences, Richmond, California, USA

› Author Affiliations

Abstract

Summary

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 P2Y₁₂ 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 P2Y₁₂ 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 FeCl₂, 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 P2Y₁₂ receptor antagonist, BX 667, has a wider therapeutic index than clopidogrel in experimental models of thrombosis.

Keywords

ADP - platelet aggregation - thrombosis - rat - dog - cyclic flow variation

Full Text

References

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