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Prostacyclin (PGI 2 ) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation, and extracellular matrix synthesis. Selexipag (Uptravi, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N -(methylsulfonyl)acetamide) is the first nonprostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy ACT-333679 (previously known as MRE-269) behaved as a full agonist in multiple PAH-relevant receptor-distal-or downstream-cellular assays with a maximal efficacy ( E  max ) comparable to that of the prototypic PGI 2 analog iloprost. In PASMC, ACT-333679 potently induced cellular relaxation (EC 50 4.3 nM) and inhibited cell proliferation (IC 50 4.0 nM) as well as extracellular matrix synthesis (IC 50 8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal-or upstream-cAMP accumulation assays ( E  max 56%) when compared with iloprost and the PGI 2 analogs beraprost and treprostinil ( E  max ∼100%). Partial agonism of ACT-333679 also resulted in limited β -arrestin recruitment ( E  max 40%) and lack of sustained IP receptor internalization, whereas all tested PGI 2 analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Selexipag Active Metabolite ACT-333679 Displays Strong Anticontractile and Antiremodeling Effects but Low<i>β</i>-Arrestin Recruitment and Desensitization Potential

Selexipag Active Metabolite ACT-333679 Displays Strong Anticontractile and Antiremodeling Effects but Lowβ-Arrestin Recruitment and Desensitization Potential