title: 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)) > prostaglandin E receptor 3 (EP(3)), IP receptor > 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(-3) 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(-4) 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.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Keith
authors.initials: K
authors.lastname: Morrison
authors.forename: Roland
authors.initials: R
authors.lastname: Ernst
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Rolf
authors.initials: R
authors.lastname: Studer
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D044006:Receptors, Epoprostenol / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000187:drug effects*
chemical_list: D000081:Acetamides; D011719:Pyrazines; D012333:RNA, Messenger; D044006:Receptors, Epoprostenol; C048081:beraprost; C016767:sulprostone; C523468:selexipag; D011464:Epoprostenol; D016285:Iloprost; D015232:Dinoprostone; C427248:treprostinil