2-[3-[2-(4,5-diphenyl-2-oxazolyl) ethyl]phenoxy] acetic acid (BMY 42393): 2) oral activity and efficacy in animal models of arterial thrombosis

Seiler, Steven M.; Buchanan, John O.; Schumacher, William A.; Zavoico, George B.; Gamberdella, M.; Fleming, John; Meanwell, Nicholas A.

doi:10.1016/0049-3848(94)90005-1

Cited by 4 publications

(8 citation statements)

References 10 publications

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“…The heterologous ex vivo platelet aggregation assay indicated that BMY 42393 was bioavailable with relative long duration of action after oral administration in the rat. These studies suggest that peak activity occurred at 6-10 h, and that the ability of the single dose to inhibit platelet function was readily apparent for more than 20 h (59).…”

Section: Heterologous Ex Vivo Platelet Aggregation Assaymentioning

confidence: 83%

“…Histological examination of the vessels confirmed the presence of plateletrich thrombi in control animals. In this model, 0.3 mg/kg of BMY 42393 by intraduodenal administration maintained a robust coronary blood flow for the duration of the experiments whereas control animals occluded (59). In these studies BMY 42393 showed no significant effects on mean arterial blood pressure (MAP), heart rate, or left ventricular contractile force during the 45 min period after drug administration but prior to application of the stenotic ring.…”

Section: Canine Coronary Artery Stenosis and Occlusionmentioning

confidence: 90%

“…These studies suggest that peak activity occurred in 6 1 0 hr, and that the ability of the single dose to inhibit platelet function was readily apparent for more than 20 h (59).…”

Section: Metabolism and Pharmacokineticsmentioning

confidence: 91%

“…The rat plasma was added to freshly prepared washed human platelets, and platelet aggregation was initiated by the addition of 10 pM ADP. The IC,, for platelet aggregation inhibition was approximately 10 mg/kg (59). The heterologous ex vivo platelet aggregation assay indicated that BMY 42393 was bioavailable with relative long duration of action after oral administration in the rat.…”

Section: Heterologous Ex Vivo Platelet Aggregation Assaymentioning

confidence: 97%

“…Because of its novel structure and partial agonist activity, BMY 42393 was studied in some detail in order to define the pharmacology and therapeutic potential of this new class of PGI, mimetic. BMY 42393 displays excellent oral bioavailability in animals, an extended duration of action, and provides effective protection in animal models of thrombosis (59) and atherosclerosis (27).…”

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confidence: 99%

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BMY 42393, An Orally Active Prostacyclin Partial Agonist Of Novel Structure

Seiler

Meanwell

1995

Cardiovascular Drug Reviews

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Prostacyclin (PGI,) is a powerful endogenous inhibitor of platelet function and a potent vasodilator that is synthesized primarily by vascular endothelial cells. Although synthetic PGI, is available for clinical administration as the sodium salt, therapeutic application has been limited by both its chemical (3,7) and metabolic instability, which necessitates constant infusion. These limitations have been largely overcome as a result of structureactivity studies that have refined the original structure into pharmaceutically useful agents. The chemical instability of the labile enol ether linkage was readily addressed by replacing the oxygen atom with a methylene, producing carbacyclin (44,69,70). Further structural modification produced ciprostene (30,46), and iloprost (20,55,56,63). While the chemical stability of these compounds represented a significant advance over the naturally occurring progenitor, they were all rapidly metabolized in vivo, leading to a relatively short duration of action. Further synthetic modification of this structural class led to the identification of other PGI, full agonists, including cicaprost (64,65), which shows some oral bioavailability and is reasonably long acting in vivo, beraprost (47), and taprostene (17,67).The pharmacological properties of these PGI, agonists are fundamentally quite similar, which is not surprising since they all were patterned after the endogenous compound (43). The initial description of a distinct class of PGI, agonist, although still structurally complex and prostanoid-like (1,75), presaged the discovery of a remarkably simple series of PGI, mimetics. The cholesterol-lowering agent octimibate (29) was recognized as the prototype of this structural class when we (57) and others (41,42) demonstrated that it behaved as a PGI, partial agonist. Although octimibate was characterized by a chemically simple, non-prostanoid structure and effectively inhibited blood platelet aggregation in vitro, it exhibited only limited ex vivo platelet inhibitory and antithrombotic activities following oral administration to animals. In an effort to identify prostacyclin mimetics with improved potency and oral bioavailability, the pharmacophore inherent to octimibate

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Section: Heterologous Ex Vivo Platelet Aggregation Assaymentioning

confidence: 83%

Section: Canine Coronary Artery Stenosis and Occlusionmentioning

confidence: 90%

“…These studies suggest that peak activity occurred in 6 1 0 hr, and that the ability of the single dose to inhibit platelet function was readily apparent for more than 20 h (59).…”

Section: Metabolism and Pharmacokineticsmentioning

confidence: 91%

Section: Heterologous Ex Vivo Platelet Aggregation Assaymentioning

confidence: 97%

mentioning

confidence: 99%

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