Details

Autor(en) / Beteiligte

• BROWNLIE, R. P.
• BROWNRIGG, N. J.
• BUTCHER, H. M.
• GARCIA, R.
• JESSUP, R.
• LEE, V. J.
• TUNSTALL, S.
• WAYNE, M. G.

Titel

ZD9583, an Orally Effective Thromboxane A2 Synthase Inhibitor and Receptor Antagonist with a Sustained Duration of Action in Rat and Dog

Ist Teil von

• Journal of pharmacy and pharmacology, 1997-02, Vol.49 (2), p.187-194

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

1997

Quelle

MEDLINE

Beschreibungen/Notizen

• The thromboxane A2 (TXA2) synthase inhibitory activity and the TXA2 receptor (TP‐receptor) blocking action of ZD9583 ((4Z)‐6‐[(2S,4S,5R)‐2‐(1‐[2‐cyano‐4‐methylphenoxy]‐1‐methylethyl)‐4‐(3‐pyridyl)‐1,3‐dioxan‐5‐yl]hex‐4‐enoic acid) has been evaluated in‐vitro by use of whole blood and platelets from man, and ex‐vivo by use of platelets and whole blood from rats and dogs. ZD9583 caused concentration–dependent inhibition of human platelet microsomal TXA2 production with an IC50 of 0.017 ± 0.003 μm; this inhibition was associated with an increase in prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) formation. ZD9583 also inhibited collagen‐stimulated TXA2 synthesis in whole blood from man, rat and dog giving IC50 values of 0.027 ± 0.005, 0002 ± 0.006 and 0.013 ± 0.01 μm, respectively. The drug did not modify platelet cyclooxygenase activity as inhibition of thromboxane B2 (TXB2) formation was associated with a concomitant increased synthesis of prostaglandin D2 (PGD2), PGE2 and PGF2α. ZD9583 had little effect on cultured human umbilical vein endothelial cell prostacyclin synthase giving an IC50 of 24.2 ± 4.9 μm. In‐vitro ZD9583 caused concentration‐dependent inhibition of U46619‐induced aggregation responses of platelets from man, rat and dog, yielding apparent log A2 values of 8.7 ± 0.12, 8.8 ± 0.2 and 9.3 ± 0.2, respectively. The drug was selective; at concentrations up to 100 μm it did not affect 5‐hydroxytryptamine or the primary phases of adenosine diphosphate and adrenaline‐induced aggregation. ZD9583 (100 μm) did not, furthermore, modify the platelet inhibitory effects of PGD2, prostaglandin E1 (PGE1) and prostacyclin. Oral administration of ZD9583 (3–10 mg kg−1) to both rats and dogs caused dose‐dependant inhibition of collagen‐stimulated TXA2 production ex‐vivo which persisted for up to 12 h. The drug also caused profound TXA2 receptor blockade in both species for in excess of 12‐h after an oral dose of 3 mg kg−1. ZD9583 (3 mg kg−1, p.o.), when administered to dogs over a five‐day period at 12 h intervals, did not cause either tachyphylaxis or an accumulation of effect. We conclude that ZD9583 is a potent, selective, orally active thromboxane synthase inhibitor and TXA2 receptor antagonist.