Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
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.
{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI 2 ) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI 2 analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E 3 (EP 3 ) receptor mRNA was increased in pulmonary artery from MCT-PAH rats.In contraction experiments, the selective EP 3 receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP 3 receptor antagonist (2E)-3-(3Ј,4Ј-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP 3 receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.
The P2Y12 receptor is a validated target for prevention of major adverse cardiovascular events in patients with acute coronary syndrome. The aim of this study was to compare two direct‐acting, reversible P2Y12 antagonists, ACT‐246475 and ticagrelor, in a rat thrombosis model by simultaneous quantification of their antithrombotic efficacy and surgery‐induced blood loss. Blood flow velocity was assessed in the carotid artery after FeCl3‐induced thrombus formation using a Doppler flow probe. At the same time, blood loss after surgical wounding of the spleen was quantified. Continuous infusions of ACT‐246475 and ticagrelor prevented the injury‐induced reduction of blood flow in a dose‐dependent manner. High doses of both antagonists normalized blood flow and completely abolished thrombus formation as confirmed by histology. Intermediate doses restored baseline blood flow to ≥65%. However, ACT‐246475 caused significantly less increase of blood loss than ticagrelor; the difference in blood loss was 2.6‐fold (P < 0.01) at high doses and 2.7‐fold (P < 0.05) at intermediate doses. Potential reasons for this unexpected difference were explored by measuring the effects of ACT‐246475 and ticagrelor on vascular tone. At concentrations needed to achieve maximal antithrombotic efficacy, ticagrelor compared with ACT‐246475 significantly increased carotid blood flow velocity in vivo (P = 0.003), induced vasorelaxation of precontracted rat femoral arteries, and inhibited contraction of femoral artery induced by electrical field stimulation or by phenylephrine. Overall, ACT‐246475 showed a significantly wider therapeutic window than ticagrelor. The absence of vasodilatory effects due to high selectivity of ACT‐246475 for P2Y12 provides potential arguments for the observed safety advantage of ACT‐246475 over ticagrelor.
Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}--(methylsulfonyl)acetamide] is a selective nonprostanoid prostacyclin (PGI) receptor (IP receptor) agonist that is approved for the treatment of pulmonary arterial hypertension (PAH). In contrast to selexipag, PGI analogs used in the clinic are nonselective agonists at prostanoid receptors and can also activate contractile prostaglandin E receptor 3 (EP) receptors. Leg pain is a common side effect in patients receiving treatment with PGI analogs and peripheral vasoconstriction can be responsible for side effects related to muscular ischemia. This study tested the hypothesis that PGI analogs could cause paradoxical vasoconstriction of the femoral artery via EP receptor activation but that only vasorelaxation would be observed in response to selexipag and its active metabolite ACT-333679 [{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid]. Selexipag and ACT-333679 relaxed rings of the isolated rat femoral artery contracted with either prostaglandin F (PGF ) or the adrenoceptor (AR) agonist phenylephrine. ACT-333679 also inhibited contraction of the femoral artery to sympathetic nerve stimulation. In contrast, PGI analogs (iloprost, beraprost, and treprostinil) caused additional contraction of arterial rings precontracted with phenylephrine, which was reverted to relaxation by antagonism of EP receptors. Treprostinil augmented contraction of the femoral artery to sympathetic nerve stimulation in an EP receptor-dependent manner. Mechanistically, concomitant EP and AR receptor activation synergistically constricted femoral arteries. It is concluded that selexipag and ACT-333679 are vasorelaxants of the rat femoral artery and, unlike PGI analogs, do not cause paradoxical vasoconstriction via activation of EP receptors. EP receptor-mediated vasoconstriction may contribute to the well documented peripheral muscle pain reported in patients with PAH receiving PGI analogs. Leg pain may be less in patients treated with selexipag.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.