Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates

Brown, George R.; Foubister, Alan J.; Hudson, Julian A.

doi:10.1111/j.2042-7158.1990.tb05349.x

Cited by 7 publications

(1 citation statement)

References 6 publications

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“…ICI 192605 is a highly selective TP receptor blocker with p A 2 of approximately 8 ( Brewster et al , 1988 ; Brown et al , 1990 ). In the present study, 8‐ iso PGE 2 ‐evoked contractions were markedly and significantly reduced by 10 −8 M ICI 192605, and abolished when the concentration of this blocker was increased 10‐fold (Figures 3 and 4), indicating that they are likely directed through TP receptors.…”

Section: Resultsmentioning

confidence: 99%

Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle

Tazzeo

Miller

Janssen

2003

British J Pharmacology

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1 We investigated the effects of five different isoprostanes (8-iso PGE 1 , 8-iso PGE 2 , 8-iso PGF 1a , 8-iso PGF 2a and 8-iso PGF 2b ) on vasomotor tone in human and porcine bronchial arterial tissues. 2 In the human bronchial arteries, 8-iso PGE 2 and 8-iso PGF 2a evoked powerful constrictions (magnitudes several fold greater than the responses to high millimolar KCl) with negative log concentration causing 50% excitation (EC 50 ) values of 6.8 and 6.5, respectively; 8-iso PGE 1 was less potent (EC 50 not calculated, since a clear peak contraction was not obtained), while the other isoprostanes were largely ineffective. In the porcine arteries, on the other hand, all three F-ring isoprostanes as well as 8-iso PGE 2 evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl-evoked response; 8-iso PGE 2 and 8-iso PGF 2a were the most potent, with negative log EC 50 values of 6.5. 3 We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8-iso PGE 2 , since this was the most potent of the isoprostanes we tested. These responses were largely reversed by the thromboxane A 2 -selective (TP) prostanoid receptor antagonist ICI 192605 (10 À8 M; 4(Z)-6-[(2,4,5 cis)2-(2-chlorophenyl)-4-(2-hydroxy phenyl)1,3-dioxan-5-yl]hexenoic acid) as well as by the nonspecific tyrosine kinase inhibitor genistein (10 À5 and 10 À4 M), and were reversed approximately 50% by the Rho-kinase inhibitor Y27632 (10 À5 M; (þ )-(R)-trans-4-(1-aminoethyl)-N-(pyridyl) cyclohexanecarboxamide dihydrochloride). 4 We conclude, therefore, that 8-iso PGE 2 constricts bronchial vasculature through the activation of TP receptors, which in turn trigger tyrosine kinase and Rho-kinase activities, resulting in powerful vasoconstriction. These findings are highly relevant to lung transplantation and to exercise-induced asthma.

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Section: Resultsmentioning

confidence: 99%