Taprostene Sodium

Abstract

In 1976 Vane, Moncada, Gryglewski, and Bunting discovered that "an enzyme isolated from arteries transforms prostaglandin peroxides to an unstable substance that inhibits platelet aggregation" (58). This endothelium-derived compound, later named prostacyclin (PGI,), turned out to be the strongest inhibitor of platelet aggregation described to date. It was further characterized as a potent vasorelaxant agent in vitro (14,22) and in vivo (3). The unique pharmacological profile of prostacyclin very soon raised many hopes as to its therapeutic potential. Prostacyclin has been tested clinically in extracorporeal circulation, cardiopulmonary bypass, peripheral arterial disease, ischemic stroke, pulmonary hypertension, congestive heart failure, and coronary artery disease (91). Further clinical development of prostacyclin was hampered, however, by its chemical and metabolic instability.To overcome these shortcomings of natural prostacyclin, many attempts have been made to synthesize analogues with improved stability. Analogues with the common feature of a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue and substitutions at or near C,, to achieve resistance against 15-hydroxyprostaglandin dehydrogenase have been described (25). Out of these series of analogues, [(5Z, 13E, 9a, 1 la, 15S)-2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanor]-prosta-5,13-dienoic acid, sodium salt (CG 4203; taprostene sodium-hereafter referred to as taprostene) (Fig. 1) yielded substantial prostacyclin activity as well as chemical and metabolic stability (10,25,34). PHARMACOLOGY Inhibition of Platelet ActivityIn hemostasis and thrombosis, activated platelets change shape, adhere to the site of the injury on a vessel wall, aggregate, and produce procoagulant activity. Inhibition of

4,5-Dihydro-1 H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) Is a Selective, Pseudo-Irreversible Orthosteric Antagonist at the Prostacyclin (IP)-Receptor Expressed by Human Airway Epithelial Cells: IP-Receptor-Mediated Inhibition of CXCL9 and CXCL10 Release

“…This lack of selectivity greatly hinders the design of experiments and interpretation of data in which the characterization of IP-receptor antagonists in a particular tissue is a primary objective. To circumvent these problems, we used in the present study the stable PGI 2 analog taprostene (Schneider et al, 1993). This ligand is selective for the IPsubtype at concentrations up to 10 M (Chan and Jones, 2004; Supplemental Fig.…”

“…Even cicaprost, which is often the agonist of choice in studies examining IP-receptor pharmacology, must be used with caution because it does not effectively discriminate IP-, EP 4 -, and, to a lesser extent, EP 3 -receptormediated responses (Abramovitz et al, 2000;Wise and Jones, 2000). To overcome these problems, we have used here a synthetic PGI 2 analog, taprostene (Schneider et al, 1993). This ligand was initially described as a full agonist (Jones et al, 1997).…”

Distinction between relaxations induced via prostanoid EP4 and IP1 receptors in pig and rabbit blood vessels

“…We also used the guinea‐pig thoracic aorta as an IP 1 preparation, based on its high sensitivity to cicaprost (Jones et al ., 1998). Two of the prostacyclin analogues proved to be of particular significance: the isocarbacyclin TEI‐9063 is a highly potent IP 1 agonist (Negishi et al ., 1991; Jones et al ., 1997) with a more flexible α‐chain than carbacyclins such as iloprost and cicaprost, while taprostene is a prostacyclin with less α‐chain flexibility due to the presence of a 1,5‐ m ‐interphenylene unit (Michel & Seipp, 1990; Schneider et al ., 1993) (Figure 1).…”

Selective Prostacyclin Receptor Agonism Augments Glucocorticoid-Induced Gene Expression in Human Bronchial Epithelial Cells

“…Even cicaprost, which is often the agonist of choice in studies examining IP-receptor pharmacology, must be used with caution at it does not definitively discriminate IP-, EP 4 -, and, to a lesser extent, EP 3 -receptor-mediated responses (41,42). To overcome these problems, we used, in the present study, a synthetic PGI 2 analog, taprostene (31). Two sets of data led us to select this ligand.…”