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

Abstract

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

Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

“…Compound 1, which has a long duration of action in animal models of thrombosis, 16 was chemically modified by replacing the oxazole ring with a pyrazine ring to obtain the lead compound, the 2-amino-5,6-diphenylpyrazine derivative 4c (Figure 1). The potency of compounds at the human IP receptor was measured by their inhibition of adenosine diphosphate (ADP)induced platelet aggregation.…”