The synthesis of a novel thromboxane receptor antagonis 4(Z)-6-(2--chlorophenyl-4--hydroxyphenyl-1,3-dioxan--5-yl) hexenoic acid ICI 192605

Brewster, Andrew G.; Brown, George R.; Foubister, Alan J.; Jessup, R.; Smithers, Michael J.

doi:10.1016/0090-6980(88)90304-8

Cited by 33 publications

(15 citation statements)

References 7 publications

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“…To establish whether TP‐receptors are involved in mediating the inhibition of EFS‐evoked [ 3 H]‐ACh release elicited by PGE 2 , PGF 2α and U46619, tissues were pretreated with the TP receptor antagonist, ICI 192, 605 (Brewster et al , 1988; 0.1 μM) for 30 min before the third EFS. As shown in Figure 3, ICI 192, 605 completely antagonized the inhibitory effect of U 46619 (1 μM) but failed to block the same response produced by PGE 2 (1 μM, 76.1 ± 10.9% inhibition before and 82.2 ± 2.7% inhibition after the antagonist, NS, n = 6) and PGF 2α , (1 μM, 32.8 ± 8.4% inhibition before and 38.1 ± 8.2% inhibition after the antagonist, NS, n = 6).…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Spicuzza

Giembycz

Barnes

et al. 1998

British J Pharmacology

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1 We have demonstrated recently that exogenous prostaglandin E 2 (PGE 2 ) inhibits electrical ®eld stimulation (EFS)-induced acetylcholine (ACh) release from parasympathetic nerve terminals innervating guinea-pig trachea. In the present study, we have attempted to characterize the pre-junctional prostanoid receptor(s) responsible for the inhibitory action of PGE 2 and to assess whether other prostanoids modulate, at a prejunctional level, cholinergic neurotransmission in guinea-pig trachea. 3 H]-ACh release when compared to receptors of the EP 3 -subtype. However, the relative importance of the dierent receptors will depend not only on the sensitivity of guinea-pig trachea to prostanoids but on the nature of the endogenous ligands released locally that have activity on parasympathetic nerves.

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Section: Resultsmentioning

confidence: 99%

Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Spicuzza

Giembycz

Barnes

et al. 1998

British J Pharmacology

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“…ICI 192605 treatment also did not alter basal airway calibre. ICI 192605 is a potent, selective and competitive TP receptor antagonist, with pA2 value of 8.16 for inhibition of human platelet aggregation induced by a thromboxane mimetic, U46619 [5]. With tracheal smooth muscle preparations, ICI 192605 was shown to block contractions induced by U-46619 and not histamine [6].…”

Section: Discussionmentioning

confidence: 99%

Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man.

Jarad

Hui

Barnes

1994

Brit J Clinical Pharma

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Many prostanoids including are prostaglandin (PG) F2 alpha and PGD2 are potent bronchoconstrictor agents. There is evidence to suggest that airway thromboxane (TP) receptor may act as a common receptor for their bronchoconstrictor actions. We tested the hypothesis that inhaled prostaglandin (PG) D2-induced bronchoconstriction is mediated by interacting with the TP receptor antagonist, ICI 192605, on the bronchoconstrictor response to inhaled PGD2 in a double-blind, placebo-controlled and crossed-over trial in normal subjects. The effect of ICI 192605 on histamine induced bronchoconstriction served as control for non-specific bronchodilatory actions. The study had two phases; the first consisted of two inhaled PGD2 challenge study days, and the second phase was that of inhaled histamine. Each study day was separated by at least a week. On each study day, the challenge tests were carried out 30 min after ingestion of 100 mg ICI 192605 or placebo. Doubling concentrations of agonist were given till more than 35% fall in post-diluent specific airway conductance (sGaw) occurred. The concentration needed to cause a fall in a sGaw of 35% post-diluent value (PC35sGaw) was then determined from linear interpolation of the log dose-response. Eight male subjects (median age 26, range 20-35 years) completed the study. ICI 192605 did not change baseline airway calibre 30 min after ingestion on either PGD2 or histamine study days. ICI 192605 significantly shifted the dose-response curve to inhaled PGD2 to the right by a median of 3.4 fold (Wilcoxon rank sign test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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“…However, despite many TP receptor antagonists having developed since the 1980s such as sulotroban (BM‐13177), daltroban (BM‐13505), ONO‐11120, ICI‐192605, GR‐32191, ONO NT‐126, KW‐3635, SQ‐29548, ifetroban (BMS‐180291), I‐SAP, LCB‐2853, linotroban (HN‐11500), Z‐335, they have polarized considerable poor interest, and their development has been stopped because of their toxicity or modest activity in clinical situations . Only ramatroban (Bay‐u3405) and seratrodast (AA‐2414) has been used clinically for the treatment of asthma in Japan since the late 1990s.…”

Section: Cyclooxygenase Products and Cardiovascular Pathophysiologymentioning

confidence: 99%

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Capra

Bäck

Barbieri

et al. 2012

Medicinal Research Reviews

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Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists.

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The synthesis of a novel thromboxane receptor antagonis 4(Z)-6-(2--chlorophenyl-4--hydroxyphenyl-1,3-dioxan--5-yl) hexenoic acid ICI 192605

Cited by 33 publications

References 7 publications

Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man.

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

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The synthesis of a novel thromboxane receptor antagonis 4(Z)-6-(2--chlorophenyl-4--hydroxyphenyl-1,3-dioxan--5-yl) hexenoic acid ICI 192605

Cited by 33 publications

References 7 publications

Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP3‐subtype

Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP3‐subtype

Effects of a thromboxane receptor antagonist on prostaglandin D2 and histamine induced bronchoconstriction in man.

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

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Product

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Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype