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Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function
Keith Morrison1, Roland Ernst, Patrick Hess
1Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Summary
Selexipag, a selective prostacyclin receptor agonist, did not affect gastric function in rats. Unlike other analogs, its selectivity may reduce gastrointestinal side effects in pulmonary arterial hypertension treatment.
Area of Science:
- Pharmacology
- Gastroenterology
- Cardiovascular Research
Background:
- Selexipag is an orally available prostacyclin (PGI(2)) receptor agonist in development for pulmonary arterial hypertension.
- Unlike PGI(2) analogs, selexipag exhibits high selectivity for the IP receptor in vitro.
- Prostacyclin analogs can activate other prostanoid receptors, potentially causing side effects.
Purpose of the Study:
- To evaluate the impact of selexipag's IP receptor selectivity on gastric function.
- To compare the effects of selexipag and other PGI(2) analogs on gastric fundus contraction ex vivo.
- To assess the influence of selexipag and analogs on gastric emptying and intestinal transport rates in vivo.
Main Methods:
- Measurement of rat gastric fundus contraction ex vivo in response to selexipag, its metabolite ACT-333679, iloprost, beraprost, and treprostinil.
- Assessment of mRNA expression of prostanoid receptors in rat gastric fundus.
- In vivo studies measuring gastric emptying and intestinal transport rates after oral administration of selexipag and beraprost.
Main Results:
- Selexipag and ACT-333679 did not induce gastric fundus contraction, unlike iloprost, beraprost, and treprostinil.
- Gastric fundus contraction induced by PGI(2) analogs was mediated by EP(3) and EP(1) receptors.
- Oral selexipag did not significantly alter gastric emptying or intestinal transport, while beraprost slowed gastrointestinal transit.
Conclusions:
- Selexipag's high functional selectivity for the IP receptor prevents gastric smooth muscle stimulation.
- This selectivity may contribute to a reduced incidence of gastric side effects like nausea and vomiting.
- Selexipag demonstrates a favorable gastric function profile compared to non-selective PGI(2) analogs.
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