A novel selective inhibitor to thrombin-induced platelet aggregation purified from the leech Whitmania pigra

Abstract Mariannaeapyrone ((E)-2-(1,3,5,7-tetramethyl-5-nonenyl)-3,5-dimethyl-6-hydroxy-4H-pyran-4-one) is a new fungal metabolite isolated from fermentations of the common mycophilic deuteromycete Mariannaea elegans. The chemical structure of the 4-pyrone was determined by spectroscopic techniques. Mariannaeapyrone is a selective inhibitor of the thromboxane A2 induced aggregation of human platelets, whereas only weak cytotoxic and antimicrobial effects could be observed.

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Synthesis and biological properties of pinane-thromboxane A2, a selective inhibitor of coronary artery constriction, platelet aggregation, and thromboxane formation.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.76.6.2566 ◽

1979 ◽

Vol 76 (6) ◽

pp. 2566-2570 ◽

Cited By ~ 70

Author(s):

K. C. Nicolaou ◽

R. L. Magolda ◽

J. B. Smith ◽

D. Aharony ◽

E. F. Smith ◽

...

Keyword(s):

Coronary Artery ◽

Platelet Aggregation ◽

Thromboxane A2 ◽

Biological Properties ◽

Selective Inhibitor ◽

Thromboxane Formation ◽

Pinane Thromboxane A2

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

Cardiovascular Drugs and Therapy ◽

10.1007/bf00054211 ◽

1988 ◽

Vol 2 (5) ◽

pp. 693-700 ◽

Cited By ~ 3

Author(s):

Tsunehiko Kuzuya ◽

Yoshihiro Kimura ◽

Shiro Hoshida ◽

Kazuhisa Kodama ◽

Nobuto Nakamura ◽

...

Keyword(s):

Platelet Aggregation ◽

Selective Inhibitor ◽

Thromboxane Synthetase

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Aggregation and/or oxygenated products of arachidonic acid are not required for collagen-induced deacylation of phosphatidylcholine in human platelets

Biochemical Journal ◽

10.1042/bj2630143 ◽

1989 ◽

Vol 263 (1) ◽

pp. 143-148 ◽

Cited By ~ 4

Author(s):

L A Piché ◽

V G Mahadevappa

Keyword(s):

Arachidonic Acid ◽

Fatty Acid ◽

Platelet Aggregation ◽

Human Platelets ◽

Selective Inhibitor ◽

Collagen Fibres ◽

Aggregation Response ◽

Severe Impairment ◽

Adhesion Of Platelets ◽

Oxygenated Products

In the present study the effects of collagen on platelet aggregation and arachidonic acid (AA) mobilization, specifically from phosphatidylcholine (PC), were investigated in the presence and absence of BW755C, a selective inhibitor of cyclo-oxygenase and lipoxygenases. The inhibition of cyclo-oxygenase and lipoxygenase(s) by BW755C (75 microM) resulted in severe impairment in collagen-induced platelet aggregation. In the presence of BW755C, the aggregation response amounted to 14, 26, 37 and 49% of the corresponding controls (without BW755C) at 10, 25, 50 and 100 micrograms of collagen respectively. On the contrary, the amount of AA released from PC, which ranged from 3.5 to 8.6 nmol/10(9) platelets, in response to the action of collagen (10-100 micrograms) remained unaffected by the presence of BW755C. Substantial amounts of non-esterified AA were detected in the free fatty acid fractions obtained from collagen-stimulated platelets in the presence as well as in the absence of BW755C. However, the presence of BW755C caused a greater accumulation of free AA (mass) and this ranged from 4 to 16 nmol, depending upon the amount of collagen. In addition, small increases in free stearic and oleic acids were observed in collagen-stimulated platelets as compared with unstimulated platelets. The amount of AA lost from PC represented 67, 80, 49 and 52% of the free AA obtained at 10, 25, 50 and 100 micrograms of collagen respectively. Our results adhesion of platelets to collagen fibres may be responsible for much of the AA release from PC Furthermore, these results demonstrate that aggregation and/or cyclo-oxygenase/lipoxygenase metabolites are not obligatory for the release of AA from PC in collagen-stimulated human platelets.

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Intravenous infusion of a selective inhibitor of thromboxane A2 synthetase in man: influence on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation.

Circulation ◽

10.1161/01.cir.70.4.599 ◽

1984 ◽

Vol 70 (4) ◽

pp. 599-605 ◽

Cited By ~ 14

Author(s):

Y Yui ◽

R Hattori ◽

Y Takatsu ◽

H Nakajima ◽

A Wakabayashi ◽

...

Keyword(s):

Platelet Aggregation ◽

Intravenous Infusion ◽

Thromboxane A2 ◽

Selective Inhibitor ◽

Thromboxane B2

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Pharmacological Profile of DZ-697b, a Novel Anti-Platelet Agent -Selective Inhibitor of vWF- and Collagen-Induced Platelet Aggregation.

Blood ◽

10.1182/blood.v106.11.1875.1875 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1875-1875 ◽

Cited By ~ 1

Author(s):

Yoshiyasu Ogihara ◽

Sumie Muramatsu ◽

Yuki Kaneda ◽

Takako Iijima ◽

Tomoko Shibutani ◽

...

Keyword(s):

Platelet Aggregation ◽

Guinea Pigs ◽

Ex Vivo ◽

Platelet Rich Plasma ◽

Thrombus Formation ◽

Bleeding Risk ◽

Selective Inhibitor ◽

Pharmacological Profile ◽

Induced Aggregation

Abstract Introduction: Bleeding risk accompanied with anti-platelet drugs is an ultimate dilemma in the treatment of thrombosis patient. Under high shear condition of blood flow, vWF- and collagen-induced signaling pathways are likely to trigger the platelet adhesion to the injured endothelium, which leads to the activation of platelets and arterial thrombus formation. Thus, the recent studies suggest that the selective inhibitor of these pathways is a new target of anti-platelet drugs with lower bleeding risk. We report here a pharmacological profile of DZ-697b, which selectively inhibits platelet aggregation evoked by ristocetin and collagen in vitro and ex vivo. Materials and methods: Human volunteers blood was processed platelet rich plasma (PRP) or washed platelets. PRP aggregation was induced by ristocetin and collagen. To reveal the selectivity, effect of DZ-697b on U46619 (TXA2 analogue), ADP, thrombin and TRAP induced aggregation in the washed platelets were examined. In guinea pigs and cynomolgus monkeys, effects of DZ-697b given orally were also examined on ex vivo PRP aggregation induced by collagen. To investigate the underlying mechanisms of DZ-697b, changes in phosphorylation of FcR γ chain, a common signaling pathway of both vWF- and collagen-induced platelet aggregation, were studied. Results: DZ-697b potently inhibited both ristocetin- and collagen-induced human PRP aggregation, the IC50 being 0.74 μM and 0.55 μM, respectively. In contrast, DZ-697b even at 50 μM did not show any influences on U46619, ADP, thrombin and TRAP induced platelet aggregation. DZ-697b did not affect ovine COX-1 and COX-2 activities at up to 300 μM. The bioavailability of this compound was more than 80% in monkeys. Oral administration of DZ-697b at 1–3 mg/kg significantly and persistently inhibited collagen induced PRP aggregation in monkeys and guinea pigs. Application of ristocetin, vWF, and collagen significantly increased the intensity of phosphorylation of FcR γ chain in washed platelets, which were inhibited by DZ-697b. Conclusion: DZ-697b is an orally active compound which selectively inhibits ristocetin- and collagen-induced platelet aggregation and seems to be promising as novel anti-platelet drug.

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Effect of Tranylcypromine on Platelet Aggregation Induced by Thrombin, ADP, Adrenaline, Collagen and Arachidonic ACID

10.1055/s-0039-1687602 ◽

1979 ◽

Author(s):

C. Busch ◽

C. Ljungman ◽

L. Birgersson

Keyword(s):

Arachidonic Acid ◽

Endothelial Cell ◽

Platelet Aggregation ◽

Thromboxane A2 ◽

Inhibitory Effect ◽

Selective Inhibitor ◽

The Other ◽

Common Pathway ◽

Prostacyclin Synthesis ◽

Platelet Functions

The monoaminooxidase inhibitor tranylcypromine has been suggested to be a selective inhibitor of prostacyclin synthetase with no inhibitory effect on thromboxane A2 formation in platelets. The substance would then be a suitable tool for discrimination between prostacyclin synthesis and release on one hand and other possible thrombocytophobic properties of the endothelial cell particularly its surface on the other. This study, however, shows that tranylcypromine interferes with platelet aggregation induced by thrombin, ADP, adrenaline and collagen whereas that of arachidonic acid is not affected. The results indicate an inhibition at an earlier common pathway of platelet aggregation than the metabolism of arachidonic acid. It is also suggested that the search for a selective inhibitor of prostacyclin synthesis which does not interfere with platelet functions should continue.

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5-Hydroxy-3-vinyl-2(5H)-furanone -a New Inhibitor of Human Synovial Phospholipase A2 and Platelet Aggregation from Fermentations of a Calyptella Species (Basidiomycetes)

Zeitschrift für Naturforschung C ◽

10.1515/znc-1995-5-611 ◽

1995 ◽

Vol 50 (5-6) ◽

pp. 403-409 ◽

Cited By ~ 3

Author(s):

Kirsten Lorenzen ◽

Timm Anke ◽

Silvia Konetschny-Rapp ◽

Werner Scheuer

Keyword(s):

Platelet Aggregation ◽

Phospholipase A2 ◽

Antimicrobial Activities ◽

Selective Inhibitor ◽

Phospholipase A ◽

Spectroscopic Methods

Abstract 5-Hydroxy-3-vinyl-2(5H)-furanone, a potent and selective inhibitor of human synovial phospholipase A2 was isolated from fermentations of a Calyptella species. Its structure as identified by spectroscopic methods is identical to PA 147, an antibiotic previously isolated from a streptomycete. 5-hydroxy-3-vinyl-2(5H)-furanone inhibits the aggregation of human and bovine platelets stimulated by different inducers and exhibits weak antimicrobial activities.

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