Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Abstract

Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI 2 ) receptor (IP receptor) agonist that is chemically distinct from PGI 2 and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI 2 can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI 2 analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP 1 ) Ͼ prostaglandin E receptor 3 (EP 3 ), IP receptor Ͼ prostaglandin D 2 receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10 Ϫ3 M. In contrast, the PGI 2 analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10 Ϫ4 M). Contraction to all PGI 2 analogs was mediated via activation of EP 3 receptors, although EP 1 receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

“…Treprostinil regulates macrophage function and promotes survival of bacteria via an EP 2 receptor-dependent mechanism (Aronoff et al, 2007). In addition, treprostinil activates contractile EP 3 receptors in gastric (Morrison et al, 2010) and vascular smooth muscle (Orie and Clapp, 2011).…”

“…Moreover, gastric side effects including cramping, nausea, and vomiting may develop via EP 3 receptor-dependent ABBREVIATIONS: PGI 2 , prostacyclin; IP receptor, PGI 2 receptor; EP 1 receptor, prostaglandin E receptor 1; EP 3 receptor, prostaglandin E receptor 3; DP 1 receptor, prostaglandin D 2 receptor 1; TP receptor, thromboxane A 2 receptor; EPA, extralobar pulmonary artery; ET-1, endothelin-1; IPA, intralobar pulmonary artery; MCT, monocrotaline; PAH, pulmonary arterial hypertension; PGF 2␣ , prostaglandin F 2␣ ; [4][5] mechanisms. Analogs of PGI 2 contract gastric smooth muscle via the stimulation of EP 3 receptors (Morrison et al, 2010). Activation of the EP 3 receptor subtype mediates disruption of gastric contractility (Pal et al, 2007;Forrest et al, 2009) and underlies the development of emesis (Kan et al, 2002).…”

“…Activation of the EP 3 receptor subtype mediates disruption of gastric contractility (Pal et al, 2007;Forrest et al, 2009) and underlies the development of emesis (Kan et al, 2002). Selexipag does not evoke gastric contraction or disrupt gastric function in the rat stomach (Morrison et al, 2010). A role for EP 3 receptors has also been invoked in the development of peripheral pain reported in patients receiving treatment with PGI 2 analogs (Minami et al, 2001;Southall and Vasko, 2001).…”

Sphingosine 1-Phosphate (S1P) Receptor Agonists Mediate Pro-fibrotic Responses in Normal Human Lung Fibroblasts via S1P2 and S1P3 Receptors and Smad-independent Signaling

“…The results were calculated with the ⌬⌬C t method and expressed as ratios of treated NHLF versus controls. For analysis of basal S1PR expression, qPCR experiments were performed as previously described (20). TaqMan assays used for mRNA detection are listed in supplemental Table S1.…”

Pathways in pulmonary arterial hypertension: the future is here

“…This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side-effects (e.g. nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimised [48]. In addition, the selexipag metabolite has a halflife of 7.9 h, thus permitting oral dosing twice daily [38].…”