Selexipag | Treatment for Pulmonary Arterial Hypertension | Treatment for PAH | Prostacyclin Receptor Agonists

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: 2D and 3D Structure

Prostacyclin Pathway and Pulmonary Arterial Hypertension

Five prostanoids, prostaglandin PGD₂, PGE₂, PGF_2α, 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:

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.

Drugs in Clinical Pipeline: SPI-026

The US Food & Drug Administration (FDA) has granted Orphan Drug Designation to Selten Pharma's lead compound tacrolimus (SPI-026) an Orphan Drug Designation for the treatment of pulmonary arterial hypertension (PAH).

SPI-026 is an investigational BMPR2 pathway activator being evaluated for the treatment of patients with pulmonary arterial hypertension. It prevented the development of PAH in mice with a deletion of BMPR2 endothelial cells in a chronic hypoxia model, and reversed PAH and neointimal/occlusion in the lungs in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. It has been shown to be safe and tolerable in patients with PAH.

An inactivating mutation in the BMPR2 gene has been linked to primary pulmonary hypertension.

What is BMPR2?

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which it phosphorylates.

What is the clinical significance of BMPR2?

BMPR2 functions to inhibit the proliferation of vascular smooth muscle tissue. It functions by promoting the survival of pulmonary arterial endothelial cells, therefore preventing arterial damage and adverse inflammatory responses. It also inhibits pulmonary arterial proliferation in response to growth factors, which prevents the closing of arteries by proliferating endothelial cells. When this gene is inhibited, vascular smooth muscle proliferates and can cause pulmonary hypertension, which, among other things, can lead to cor pulmonale, a condition that causes the right side of the heart to fail. The dysfunction of BMPR2 can also lead to an elevation in pulmonary arterial pressure due to an adverse response of the pulmonary circuit to injury.

Further Read:

1. Gilboa, L.; et. al. Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 2000,

11(3), 1023-1035.

2. Rabinovitch, M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012, 122(12), 4306-4313.

3. Selten Pharma is a privatively held biopharmaceutical company formed in 2013 that is focused on the development and commercialization of therapies for the treatment of rare diseases.