Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue

doi:10.1016/0090-6980(83)90105-3

Prostaglandins

Volume 25, Issue 2, February 1983, Pages 205-223

Prostaglandins

https://doi.org/10.1016/0090-6980(83)90105-3 Get rights and content

Abstract

The platelet anti-aggregating, cardiovascular and gastro-intestinal actions of a hydantoin prostaglandin analogue, BW245C have been compared with prostaglandin and PGD₂ several species. In human plasma $in vitro$ , BW245C was 0.2 times as active as prostacyclin and 8 times as active as PGD₂ in inhibiting platelet aggregation. In rat and rabbit plasma, BW245C was only weakly active but was more potent in sheep and horse plasma. Since the acivity of PGD₂ varied in a parallel fashion, BW245C may interactive with PGD₂ binding sites on platelets. The potency of BW245C as a vasodepressor also varied between species, being 0.5, 0.1, 0.06 and < 0.02 times as active as prostacyclin in the aneasthetised dog, monkey, rat and rabbit respectively.

The relative activity of BW245C as an inhibitor of platelet aggregation $ex vivo$ was more comparable, being 0.08, 0.04 and 0.05 times as active as prostacyclin following intravenous infusion in the rabbit dog and monkey respectively. In the rabbit, BW245C was a highly selective platelet inhibitor with minimal cardiovascular actions, whereas in the dog and monkey, BW245C lowered BP in anti-aggregating doses. The potent platlet anti-aggregating actions of BW245C following parenteral or oral administration makes this hydantoin a potentially-useful anti-thrombotic prostaglandin analogue.

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PGD<inf>2</inf> DP1 receptor stimulation following stroke ameliorates cerebral blood flow and outcomes
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Citation Excerpt :
Therefore, we believe that poor CBF restoration after reperfusion as observed in the vehicle group could be due to any of these events, whereas the DP1 agonist counters these effects and improves CBF. This conviction is further supported by the fact that PGD2 and the DP1 agonists inhibit platelet aggregations, which are one of the prime factors in forming atherosclerosis plaque and resulting in hypoperfusion (Whittle et al., 1983; Schuligoi et al., 2007). Another factor leading to better CBF after BW245C treatment could be the interaction of arterioles with astrocytes and neurons in brain parenchyma.
Stroke is a leading cause of death and morbidity worldwide, yet effective treatments are lacking. The association of prostaglandin D₂ and its DP1 receptor with vasculature and blood propelled us to examine whether the clinically tested DP1 receptor agonist BW245C had beneficial effects following stroke. To determine if BW245C affects basal cerebral blood flow (CBF), C57BL/6 WT and DP1^−/− mice were given a single i.p. injection of vehicle or BW245C, and CBF was recorded for 2 h. To test the effect of BW245C on stroke, WT and DP1^−/− mice were subjected to middle cerebral artery occlusion followed by a single i.p. injection of vehicle or 0.02, 0.2, or 2.0-mg/kg BW245C immediately before reperfusion. Functional and anatomical outcomes were determined at 96 h. We also determined the effect of BW245C on CBF in peri-infarct and core during occlusion and reperfusion. Furthermore, we tested the effect of BW245C on bleeding time and ex vivo coagulation. BW245C treatment increased the basal CBF significantly in WT but not in DP1^−/− mice. The BW245C treatment also significantly improved functional outcome and lowered infarction volume. The multisite CBF monitoring by laser-Doppler flowmetry shows that BW245C significantly increased the CBF in peri-infarct, with a significant inverse correlation between infarction and CBF. The significantly higher infarction volume in DP1^−/− mice remained unchanged with BW245C treatment. Moreover, BW245C preserves hemostasis in non-stroke conditions. Combined, these data suggest that the DP1 receptor is an endogenous target that can rescue the brain following stroke by regulating CBF and hemostasis.
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Prostanoids, which consist of prostaglandins (PGs) and thromboxanes (TXs), are biologically synthesized in the body from arachidonic acid by cyclooxygenase, PG hydroperoxydase, and a family of prostaglandin synthases. They exert a variety of actions as hormones produced locally in various tissues and cells to maintain homeostasis. Research directed toward understanding the physiological and pharmacological roles of prostanoids has stimulated drug development of natural or synthetic analogs in the broad range of therapeutic areas. One of the main problems with the natural prostanoids as drugs has been perceived to be both chemical and metabolic instability. The prostanoids have been thought to exert their multiple physiological actions via specific protein receptors on the surface of target cells. Prostanoids themselves are regarded as lipophilic molecules, but the enhancement in lipophilicity introducing a fluorinated building block as a rigid template may be an effective methodology to increase the specific affinity to a hydrophobic pocket of the receptors. The involvement of prostanoid receptors in broad areas of pathological phenomena has drawn much attention and explored their potential use as a therapeutic target in intractable diseases. In addition, identification and characterization of prostanoid transporters are expected to be informative to design a new formulation for drug targeting or drug delivery system. The fluorinated prostanoids may also be useful as a new probe in spectroscopic analysis on drug–receptor interactions by nuclear magnetic resonance or molecular imaging in vivo using positron emission tomography.
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Functional pharmacology of human prostanoid EP <inf>2</inf> and EP <inf>4</inf> receptors
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Prostanoid EP₂ and EP₄ receptor-mediated responses are difficult to distinguish pharmacologically because of the lack of potent, selective antagonists. We describe systematic agonist fingerprints for recombinant human prostanoid EP₂ and EP₄ receptors expressed in CHO and HEK293 cells, respectively. The rank orders of potency of endogenous prostaglandins were: prostanoid EP₂ receptors: prostaglandin E₂≫prostaglandin D₂=prostaglandin F_2α>prostaglandin I₂; prostanoid EP₄ receptors: prostaglandin E₂≫prostaglandin I₂>prostaglandin D₂=prostaglandin F_2α. Butaprost free acid (9-oxo-11α,16R-dihydroxy-17-cyclobutyl-prost-13E-en-1-oic acid) behaved as a highly selective partial agonist at prostanoid EP₂ receptors while butaprost methyl ester elicited small, low potency responses. The prostanoid EP₁ and EP₃ receptor agonists misoprostol (9-oxo-11α,16-dihydroxy-16-methyl-prost-13E-en-1-oic acid, methyl ester), sulprostone (N-(methylsulphonyl)-9-oxo-11α,15R-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-5Z,13E-dien-1-amide), and GR63799X ([1R-[1α(Z),2β(R*),3α]-(-)-4-benzoylamino)phenyl-7-[3-hydroxy-3-phenoxy-propoxy)-5-oxocyclopentyl]-4-heptenoate), and the prostanoid DP receptor agonist BW245C ((4S)-(3-[(3R,S)-3-cyclohexyl-3-hydropropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), activated both prostanoid EP₂ and EP₄ receptors. Prostaglandin I₂, iloprost (6,9α-methylene-11α,15S-dihydroxy-16-methyl-prosta-5E,13E-dien-18-yn-1-oic acid, trometamol salt) and cicaprost (5-[(E)-(1S, 5S, 6S, 7R)-7-hydroxy-6-[(3S, 4S)-3-hydroxy-4-methylnona-1,6-diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid; ZK96480) were full agonists at prostanoid EP₄ receptors. Key differentiating agonists are: butaprost FA, 16,16-dimethyl-prostaglandin E₂, 19-(R)-hydroxy prostaglandin E₂, misoprostol, BW245C, prostaglandin F_2α and prostaglandin D₂.
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Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue

Abstract

Prostaglandins

J. Biol. Chem.

Prostaglandins

Eur. J. Pharamacol.

Prostaglandins

Prostaglandins

Prostaglandins

An enzyme isolated from arteries transforms prostaglandin endeperoxides to an unstable substance that inhibits platelet aggregation

Nature

Prostaglandin D2 inhibits the aggregation of human platelets

Thromb. Res.

Selective binding site for [3H] prostacyclin on platelets

J. Clin. Invest.

Prostaglandin D₂ inhibits the aggregation of human platelets

Selective binding site for [³H] prostacyclin on platelets