Antagonists of the EP₃ Receptor for Prostaglandin E₂ Are Novel Antiplatelet Agents That Do Not Prolong Bleeding

Abstract

Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…PGE 2 exerts a dual action on platelets, inhibition at high doses, and potentiation of the effect of proaggregatory agents (Armstrong, 1996). This potentiating effect was ascribed to EP 3 receptors (Matthews and Jones, 1993), which has been amply confirmed (Fabre et al, 2001;Ma et al, 2001;Gross et al, 2007;Singh et al, 2009). EP 3 agonists have been shown to reduce infarct size and reduce myocardial injury (Zacharowski et al, 1999;Hohlfeld et al, 2000), with supportive evidence from cardiospecific EP 3 receptor overexpression .…”

“…They are both highly lipophilic with slow onsets on certain isolated smooth muscle preparations (Jones et al, 2008). The related EP 3 antagonist DG-041 (Heptinstall et al, 2008;Singh et al, 2009) is even more lipophilic (log P ϭ 7.67); affinity is maintained when the acryloyl unit is replaced by a heterocycle (Fig. 5, Hategan et al, 2009).…”

“…EP 2 receptor deficiency decreased the growth, angiogenesis, and metastasis of mammary tumors in mice; increased EP 2 receptor expression by TGF␤ increased mammary epithelial cell invasion, growth, and resistance to TGF␤-mediated cytostasis (Tian and Schiemann, 2010). Proliferation of squamous cell carcinoma has been ascribed to EP 2 receptors (Donnini et al, 2007;Yu et al, 2008aYu et al, , 2009. PPAR␥ ligands were shown to inhibit lung carcinoma cell proliferation by suppressing EP 2 receptor expression (Han and Roman, 2004).…”

“…These include pain and inflammation (Jones et al, 2009), type 1 allergy (Nguyen et al, 2002), lung infection ), cough (Maher et al, 2009), overactive bladder PROSTAGLANDIN RECEPTORS (McCafferty et al, 2008;Su et al, 2008), hyperpyrexia , and cancer (Amano et al, 2003). Most recently, EP 3 antagonists have emerged as a new target for antiplatelet agents in atherothrombotic disease, without prolonged bleeding (Heptinstall et al, 2008;Singh et al, 2009 . The pharmacologically defined EP 4 receptor was originally designated EP 2 Bastien et al, 1994) until the authentic EP 2 receptor was cloned (Regan et al, 1994b).…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…338 There exists a complex network of signaling events that govern platelet activation and aggregation and great strides have been made in modulating these relevant signaling events to avoid catastrophic acute thrombosis during vascular events like myocardial infarction and stroke. The recognition that aspirin (acetylsalicylic acid) acts as an antagonist of platelet aggregation can be considered a starting point for research into defining the critical targets associated with platelet function.…”