Selexipag
[2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is a first-in-class orally available, potent
and selective non-prostanoid Prostacyclin (PGI2) receptor agonist, which exerts vasodilating
effects. It is designed with purpose to answer some of the pharmacokinetic and
safety limitations associated with prostacyclin analogs. Selexipag
was developed for the treatment of pulmonary arterial hypertension (PAH) and
shown to reduce the risk of the composite morbidity/mortality end point in a
phase 3 event-driven clinical trial [1].
Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both Selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with Selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the Selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily [1].
Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both Selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with Selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the Selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily [1].
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| Selexipag: 2D and 3D Structure |
Prostacyclin Pathway and Pulmonary Arterial Hypertension
Five prostanoids, prostaglandin PGD2, PGE2, PGF2α, prostacyclin (PGI2) and thromboxane A2 (TXA2), are cyclooxygenase metabolites of arachidonic acid. Prostacyclin (PGI2) is an endogenous prostanoid synthesized mainly by vascular endothelial cells. PGI2 is a potent vasodilator and inhibitor of platelet aggregation.
A dysregulation of prostacyclin pathways has been implicated in the pathogenesis of PAH and provides the rationale for the use of prostacyclin analogs in its treatment.
Relation with Metabolite
Dosages and Approval
Selexipag (Tradename: Uptravi) was discovered by Nippon Shinyaku Co., Ltd. and developed for the treatment of PAH by Nippon Shinyaku and Actelion Pharmaceuticals Ltd. The recommended starting dosage of Selexipag is 200 mcg twice daily. The dosage is increased in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dosage (up to 1,600 mcg twice daily). Though, tolerability may be improved when the drug is taken with food but if a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
Summary
Common name: ACT-293987; ACT293987; ACT 293987, NS-304; NS304;
NS 304
Trademarks: Uptravi
Molecular Formula: C26H32N4O4S
CAS Registry Number: 475086-01-2
CAS Name: 2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
Molecular Weight: 496.6
SMILES:CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3
InChI Key: QXWZQTURMXZVHJ-UHFFFAOYSA-N
InChI: InChI=1S/C26H32N4O4S/c1-20(2)30(16-10-11-17-34-19-24(31)29-35(3,32)33)23-18-27-25(21-12-6-4-7-13-21)26(28-23)22-14-8-5-9-15-22/h4-9,12-15,18,20H,10-11,16-17,19H2,1-3H3,(H,29,31)
Mechanism
of Action: Nonprostanoid IP Prostacyclin Receptor Agonist
Activity: Treatment of Pulmonary Arterial Hypertension;
Treatment of PAH;
Cardiac Therapy; Antihypertensives; Antineoplastic Agents; Respiratory System
Products
Status: Launched 2015 (US)
Chemical
Class: Diphenylpyrazine derivatives; Pyrazines; Small-molecules; N-acylsulfonamides
Originator: Actelion Pharmaceuticals/Nippon Shinyaku
Selexipag synthesis
Bioorg Med Chem 2007, 15, 6692-6704: This is the first reported synthesis for Selexipeg. Ref 3 summarizes the same.
Identifications:
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| 1H NMR (Estimated) for Selexipag |
Experimental: 1H NMR
(CDCl3) δ: 1.29 (6H, d, J =
6.6 Hz), 1.60-1.90 (4H, m), 3.29 (3H, s), 3.46 (2H, t, J = 7.3 Hz), 3.59 (2H,
t, J = 6.0 Hz), 3.97 (2H, s), 4.72 (1H, qn, J = 6.6 Hz), 7.15-7.50 (10H, m),
8.02 (1H, s).
Sideeffects:
The most common reported
advese events (AEs) by Selexipag group compared with placebo were headache
(66.6 vs 20%), pain in jaw (36.4 vs 0%), pain in an extremity (30.3 vs 0%),
nausea (27.3 vs 0%) and nasopharyngitis (24.2 vs 20%). Prevalence of adverse
events associated with prostacyclin analog treatment decreased over time in
patients treated with Selexipag.
If signs of pulmonary edema occur, clinicians should consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, Uptravi should be discontinued.
References:
1. Skoro-Sajer, N.; et. al. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2014, 15(3), 429-436.
2. Asaki, T.; et. al. Structure-activity studies on diphenylpyrazine derivatives: a novel class of prostacyclin receptor agonists. Bioorg Med Chem 2007, 15(21), 6692-6704.
3. Asaki, T.; et. al. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension. J Med Chem 2015, 58(18), 7128-7137.
1. Skoro-Sajer, N.; et. al. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2014, 15(3), 429-436.
2. Asaki, T.; et. al. Structure-activity studies on diphenylpyrazine derivatives: a novel class of prostacyclin receptor agonists. Bioorg Med Chem 2007, 15(21), 6692-6704.
3. Asaki, T.; et. al. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension. J Med Chem 2015, 58(18), 7128-7137.
