Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function.
The Journal of pharmacology and experimental therapeutics 2010 Jul 21; In press
Morrison K, Ernst R, Hess P, Studer R, Clozel M
Actelion Pharmaceuticals Ltd.
Selexipag is an orally available prostacyclin receptor (IP receptor) agonist that is chemically distinct from prostacyclin 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 prostacyclin 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 to other prostacyclin analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: EP(1) > EP(3), IP > DP(1), TP. Selexipag and metabolite ACT-333679 did not contract gastric fundus at concentrations up to 10(-3) M. In contrast, the prostacyclin analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10(-4) M). Contraction to all prostacyclin analogs was mediated via activation of EP(3) receptors, although EP(1) receptors also contributed to 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 gastro-intestinal 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.
Keywords: prostacyclin Selexipag