Cv-4151 — a potent, selective thromboxane A2synthetase inhibitor

Terashita, Zen‐ichi; Imura, Yoshimi; Tanabe, Masao; Kawazoe, K; Nishikawa, Kohei; Kato, Keita; Terao, Shinji

doi:10.1016/0049-3848(86)90231-8

Cited by 31 publications

(10 citation statements)

References 16 publications

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“…In a part of the experiments, the cyclooxygenase inhibitor indomethacin (10~5 M), 22 -24 thromboxane A 2 synthetase inhibitor (E)-7-phenyl-7-(3-pyridyl)-6-heptanoic acid (CV-4151) (10~5 M) 25 or prostaglandin I 2 synthetase inhibitor tranylcypromine (10~4 M) 26 was incubated in the solution 30 minutes before and during the response to acetylcholine. Basal tension and norepinephrineinduced contractions were not significantly affected by these inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat.

et al. 1989

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This study was undertaken to compare age-related changes in endothelium-dependent vascular responses in both hypertensive and normotensive rats. Aorta from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) aged 4-6 weeks (young), 3-6 months (adult), and 12-25 months (old) were examined for relaxation to acetylcholine, adenosine 5'-triphosphate (ATP), and sodium nitroprusside. Rubbed (endothelium denuded) aorta from all groups displayed neither relaxation nor contraction to acetylcholine. Maximal relaxation responses to acetylcholine were reduced progressively with increasing age in unrubbed aorta of both SHR and WKY rats. In addition, acetylcholine caused not only dose-dependent relaxations at lower concentrations but also increases in tension at higher concentrations in unrubbed aorta of old WKY rats as well as adult and old SHR. However, indomethacin completely inhibited the tension development. As a result, aorta treated with indomethacin demonstrated similar acetylcholine-induced, endothelium-dependent relaxations in all groups. The thromboxane A 2 synthetase inhibitor (E)-7-phenyl-7-(3-pyridyl)-6-heptanoic acid (CV-4151) partially but significantly depressed the increases in tension in aorta of old WKY rats. The degrees of endothelium-dependent relaxations to ATP and endothelium-independent relaxations to sodium nitroprusside were almost similar in all groups. These findings suggest that the release of or vascular responsiveness to endothelium-derived relaxing factor in the aorta is well maintained through senescence in both strains and that, in the aorta of not only SHR but also old normotensive WKY rats, the endothelium releases contracting factors that may be thromboxane A 2 and other vasoconstrictor prostanoids. (Hypertension 1989;14:542-548)

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Section: Methodsmentioning

confidence: 99%

Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat.

et al. 1989

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“…Though this compound inhibited thromboxane synthetase strongly, it caused no changes in PGI z synthetase, cyclooxygenase, and lipoxygenase activities [13]. It exhibited a potent and continuous inhibition of TXA 2 production, an enhancement of PGI2 production [13], an inhibition of platelet aggregation, antithrombogenesis, suppression of coronary vasospasm, and a protective effect on ischemic myocardium in the rat, rabbit, and dog [14] without any harmful effect or drug retention even in long-term dosing.…”

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confidence: 99%

The effect of CV-4151, a selective inhibitor of thromboxane synthetase, on prostanoid formation and platelet aggregation in humans

Kuzuya

Kimura²,

Hoshida³

et al. 1988

Cardiovasc Drug Ther

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The pharmacokinetics and pharmacologic effects of a potent, selective inhibitor of thromboxane synthetase, CV-4151 [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid] on prostanoid formation and platelet aggregation were studied in 42 healthy male volunteers. The drug was well tolerated. After oral administration of 10 to 100 mg of CV-4151, peak plasma levels of 1-6 micrograms/mL were reached in a dose-dependent manner within 1 hour. Elimination followed first-order fashion with elimination half-life of about 1 hour. Serum levels of thromboxane B2 reduced to 4% to 15% of control at 2 hours after drug ingestion dose-dependently. Serum levels of 6-keto-prostaglandin F1 alpha increased to about four to six times basal levels. Platelet aggregation induced by collagen and arachidonate was inhibited in most cases. Such pharmacologic effects outlasted serum drug levels. In repeated administration, stable inhibition of serum thromboxane B2 production and platelet aggregation in proportion to the enhancement of serum 6-keto-prostaglandin F1 alpha production was observed although no drug accumulation was found. These results indicate that CV-4151 may be suitable for clinical trials in cardiovascular diseases in which imbalance between thromboxane and prostacyclin may be involved in the pathogenesis.

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“…We have already reported that CV-41 51 [(E) 7 phenyl 7 (3-pyridyl) 6 heptenoic acid], a TXA2 synthetase inhibitor, has a TXA2/PGH2 antagonistic action (6,7), and shows an antithrombotic effect and protective effect on the experimental myocardial infarc tion (8,9). Recently, we synthesized a novel * To whom all correspondence should be addressed .…”

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Antagonistic action of AA-2414 on thromboxane A2/prostaglandin endoperoxide receptor in platelets and blood vessels.

et al. 1990

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Cv-4151 — a potent, selective thromboxane A2synthetase inhibitor

Cited by 31 publications

References 16 publications

Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat.

Age and hypertension promote endothelium-dependent contractions to acetylcholine in the aorta of the rat.

The effect of CV-4151, a selective inhibitor of thromboxane synthetase, on prostanoid formation and platelet aggregation in humans

Antagonistic action of AA-2414 on thromboxane A2/prostaglandin endoperoxide receptor in platelets and blood vessels.

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