Prostanoid receptor antagonists: development strategies and therapeutic applications

Abstract

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 . . .) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

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

“…2). Second, the ability of taprostene to enhance GRE-dependent transcription in BEAS-2B reporter cells was antagonized in a competitive manner by RO3244794, an IP-receptor-blocking drug, with an affinity (pK b ϭ 9.21) consistent with an interaction at IP-receptors (27,43). Collectively, these results strongly suggest that in BEAS-2B cells, taprostene augments GRE-dependent transcription by an IPreceptor-mediated mechanism.…”

Roles of Prostaglandin E2 in Cardiovascular Diseases

“…[15][16][17] Mizuguchi, et al revealed that myoelectrical activity was suppressed by continuous infusion of ONO-DI-004 into the gastric artery. This demonstrates that EP1 signaling has a crucial role in the suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying.…”

“…19) ii) EP2 agonists: ONO-AE1-259, CP-533536, 19(R)-hydroxy PGE 2 , AH13205 and misoprostol are known as major EP2 agonists. 16,17) Among them, ONO-AE1-259 has been widely used to clarify the roles of EP2 ( Figure 1C). This compound reduced the infarct volume correlated with improved neurologic scores in mice.…”

“…26) iii) EP3 agonists: ONO-AE-248, sulprostone, SC-46275, MB-28767, GR-63799, and misoprostol are known as major EP3 agonists. 16,17) In this group, ONO-AE-248 and sulprostone have been investigated to clarify the roles of EP3 (Figures 1 D and E). Recently, it was reported that ONO-AE-248 augmented glutamate-induced excitotoxicity in CA1 neurons.…”

“…32) Signaling experiments revealed that MB28767 inhibited forskolin-induced cAMP concentrations in Chinese hamster ovary cells. 33) iv) EP4 agonists: ONO-AE1-329 and cicaprost 16,17) are well known selective EP4 agonists (Figures 1 F and G). ONO-AE1-329 induced potent vasodilatation of the human pulmonary vein and relaxations induced by PGE 2 .…”