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ZD1542, a potent thromboxane A 2 synthase inhibitor and receptor antagonist in vitro
Author(s) -
Brownlie R.P.,
Brownrigg N.J.,
Butcher H.M.,
Garcia R.,
Jessup R.,
Lee V.J.,
Tunstall S.,
Wayne M.G.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb14007.x
Subject(s) - thromboxane a synthase , antagonist , pharmacology , chemistry , in vitro , thromboxane receptor , thromboxane a2 , atp synthase , receptor antagonist , receptor , endocrinology , biochemistry , medicine , enzyme
1 The thromboxane A 2 synthase (TXS) inhibitory activity and the thromboxane A 2 (TP)‐receptor blocking action of ZD1542 (4(Z)‐6‐[2S,4S,5 R )‐2‐[1‐methyl‐1‐(2‐nitro‐4‐tolyloxy)ethyl]‐4‐(3‐pyridyl)‐1,3‐dioxan‐5‐yl]hex‐4‐enoic acid) has been evaluated in vitro on platelets and whole blood from a range of species including man. Antagonist activity has also been investigated in vascular and pulmonary smooth muscle preparations in vitro.2 ZD1542 caused concentration‐dependent inhibition of human platelet microsomal thromboxane B 2 (TXB 2 ) production in vitro (IC 50 = 0.016 μ m ); this inhibition was associated with an increase in prostaglandin E 2 (PGE 2 ) and PGF 2α formation. 3 ZD1542 also inhibited collagen‐stimulated TXS in human, rat and dog whole blood giving IC 50 values of 0.018, 0.009 and 0.049 μ m respectively. The drug did not modify platelet cyclo‐oxygenase activity as inhibition of TXB 2 formation was associated with a concomitant increase in the levels of PGD 2 , PGE 2 and PGF 2α . ZD1542 had little if any effect against cultured human umbilical vein endothelial cell (HUVEC) cyclo‐oxygenase (IC 50 > 100 μ m ) and prostacyclin (PGI 2 ) synthase (IC 50 = 18.0 ± 8.6 μ m ). 4 ZD1542 caused concentration‐dependent inhibition of U46619‐induced aggregation responses of human, rat and dog platelets yielding apparent pA 2 values of 8.3, 8.5 and 9.1 respectively. The drug was selective as, at concentrations up to 100 μ m , it did not modify 5‐hydroxytryptamine (5‐HT) or the primary phases of adenosine diphosphate (ADP) and adrenaline‐induced aggregation. Furthermore, ZD1542 (100 μ m ) modified only weakly the platelet inhibitory effects of PGD 2 , PGE 1 and PGI 2 . 5 ZD1542 also caused concentration‐dependent inhibition of U46619‐mediated contractions of rat thoracic aorta, guinea‐pig trachea and lung parenchyma preparations giving apparent pA 2 values of 8.6, 8.3 and 8.5 respectively. At concentrations approaching three orders of magnitude greater than those required to block U46619‐mediated contractions, the drug did not affect the actions of non‐prostanoid agonists or exhibit agonist activity in any of the smooth muscle preparations employed; neither did it interact at EP‐ or FP‐receptors. 6 In conclusion, the present study demonstrates that ZD1542 is a drug that exhibits both potent, selective TXS inhibition and TXA 2 receptor antagonism.