Identification

Name
Selexipag
Accession Number
DB11362
Type
Small Molecule
Groups
Approved
Description

Selexipag was approved by the United States FDA on December 22, 2015 for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization. PAH is a relatively rare disease with usually a poor prognosis requiring more treatment options to prolong long-term outcomes. Marketed by Actelion Pharmaceuticals under brand name Uptravi, selexipag and its active metabolite, ACT-333679 (MRE-269), act as agonists of the prostacyclin receptor to increase vasodilation in the pulmonary circulation and decrease elevated pressure in the blood vessels supplying blood to the lungs.

Structure
Thumb
Synonyms
Not Available
External IDs
ACT-293987 / NS-304
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
UptraviTablet, film coated1400 μgOralActelion Registration Ltd2016-05-12Not applicableEu
UptraviTablet800 mcgOralActelion2016-04-21Not applicableCanada
UptraviTablet, film coated800 μgOralActelion Registration Ltd2016-05-12Not applicableEu
UptraviTablet200 mcgOralActelion2016-04-21Not applicableCanada
UptraviTablet, coated1400 ug/1OralActelion2015-12-21Not applicableUs
UptraviTablet, film coated400 μgOralActelion Registration Ltd2016-05-12Not applicableEu
UptraviTablet, coated800 ug/1OralActelion2015-12-21Not applicableUs
UptraviTablet, film coated200 μgOralActelion Registration Ltd2016-05-12Not applicableEu
UptraviTablet, coated200 ug/1OralActelion2015-12-21Not applicableUs
UptraviTablet1200 mcgOralActelion2016-04-21Not applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
UPTRAVI Titration PackSelexipag (200 ug/1) + Selexipag (800 ug/1)KitActelion2015-12-21Not applicableUs
UPTRAVI Titration PackSelexipag (200 ug/1) + Selexipag (800 ug/1)KitActelion2015-12-21Not applicableUs
Categories
UNII
5EXC0E384L
CAS number
475086-01-2
Weight
Average: 496.63
Monoisotopic: 496.2144267
Chemical Formula
C26H32N4O4S
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)
IUPAC Name
2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-methanesulfonylacetamide
SMILES
CC(C)N(CCCCOCC(=O)NS(C)(=O)=O)C1=NC(C2=CC=CC=C2)=C(N=C1)C1=CC=CC=C1

Pharmacology

Indication

Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization.

Associated Conditions
Pharmacodynamics

At the maximum tolerated dose of 1600 mcg twice per day, selexipag was not found to prolong the QT interval to a clinically relevant extent. Both selexipag and its metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters following multiple dose administration of selexipag in healthy patients.

Mechanism of action

Selexipag is a selective prostacyclin (IP, also called PGI2) receptor agonist. The key features of pulmonary arterial hypertension include a decrease in prostacyclin and prostacyclin synthase (enzyme that helps produce prostacyclin) in the lung. Prostacyclin is a potent vasodilator with anti-proliferative, anti-inflammatory, and anti-thrombotic effects; therefore, there is strong rationale for treatment with IP receptor agonists. Selexipag is chemically distinct as it is not PGI2 or a PGI2 analogue and has high selectivity for the IP receptor. It is metabolized by carboxylesterase 1 to yield an active metabolite (ACT-333679) that is approximately 37 times more potent than selexipag. Both selexipag and its metabolite are selective for the IP receptor over other prostanoid receptors.

TargetActionsOrganism
AProstacyclin receptor
agonist
Human
Absorption

After oral administration, maximum concentrations of selexipag and its metabolite were observed to be reached at 1-3 and 3-4 hours, respectively. Absorption was impaired in the presence of food, resulting in delayed time to maximum concentration as well as ~30% lower peak plasma concentration. However, exposure was not found to be significantly affected by food.

Volume of distribution
Not Available
Protein binding

Both selexipag and its active metabolite are highly protein bound, approximately 99%.

Metabolism

Selexipag yields its active metabolite by hydrolysis of the acylsulfonamide by the enzyme hepatic carboxylesterase 1. Oxidative metabolism catalyzed by CYP3A4 and CYP2C8 results in hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Other than active metabolite, other metabolites in circulation do not exceed 3% of the total drug-related material.

Route of elimination

93% in feces, 12% in urine.

Half life

Selexipag's terminal half life is 0.8-2.5 hours. The active metabolite's terminal half life is 6.2-13.5 hours.

Clearance

On average, 35 L/hour.

Toxicity

A 40-70% increase in exposure was observed in subjects with severe renal impairment.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Selexipag.
AbirateroneThe serum concentration of Selexipag can be increased when it is combined with Abiraterone.
AcebutololAcebutolol may increase the hypotensive activities of Selexipag.
AcemetacinThe therapeutic efficacy of Selexipag can be decreased when used in combination with Acemetacin.
AcetaminophenThe serum concentration of Selexipag can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Selexipag can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe therapeutic efficacy of Selexipag can be decreased when used in combination with Acetylsalicylic acid.
AlbendazoleThe serum concentration of Selexipag can be increased when it is combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Selexipag.
AlfuzosinAlfuzosin may increase the hypotensive activities of Selexipag.
Food Interactions
No interactions found.

References

General References
  1. Sharma K: Selexipag for the treatment of pulmonary arterial hypertension. Expert Rev Respir Med. 2016 Jan;10(1):1-3. doi: 10.1586/17476348.2016.1121103. Epub 2015 Dec 7. [PubMed:26567613]
  2. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, Mukai H: Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag. Am J Cardiovasc Drugs. 2015 Jun;15(3):195-203. doi: 10.1007/s40256-015-0117-4. [PubMed:25850750]
External Links
KEGG Drug
D09994
PubChem Compound
9913767
PubChem Substance
310265229
ChemSpider
8089417
ChEBI
90844
ChEMBL
CHEMBL238804
Drugs.com
Drugs.com Drug Page
Wikipedia
Selexipag
ATC Codes
B01AC27 — Selexipag
AHFS Codes
  • 48:48.00 — Vasodilating Agents
FDA label
Download (768 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableBioequivalence1
1CompletedNot AvailableCardiodynamics / Pharmacokinetics / Safety / Tolerability1
1CompletedNot AvailableHealthy Volunteers3
1CompletedOtherHealthy Volunteers2
2CompletedTreatmentRaynaud's Phenomenon Secondary to Systemic Sclerosis1
2RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
3Active Not RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
3CompletedTreatmentPulmonary Arterial Hypertension (PAH)3
3RecruitingTreatmentPulmonary Arterial Hypertension (PAH)1
4RecruitingOtherPulmonary Arterial Hypertension (PAH)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral1000 mcg
TabletOral1200 mcg
TabletOral1400 mcg
TabletOral1600 mcg
TabletOral200 mcg
TabletOral400 mcg
TabletOral600 mcg
TabletOral800 mcg
Tablet, coatedOral1000 ug/1
Tablet, coatedOral1200 ug/1
Tablet, coatedOral1400 ug/1
Tablet, coatedOral1600 ug/1
Tablet, coatedOral200 ug/1
Tablet, coatedOral400 ug/1
Tablet, coatedOral600 ug/1
Tablet, coatedOral800 ug/1
Tablet, film coatedOral1000 μg
Tablet, film coatedOral1200 μg
Tablet, film coatedOral1400 μg
Tablet, film coatedOral1600 μg
Tablet, film coatedOral200 μg
Tablet, film coatedOral400 μg
Tablet, film coatedOral600 μg
Tablet, film coatedOral800 μg
Kit
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7205302No2003-04-042023-04-04Us
US9173881No2009-08-122029-08-12Us
US9284280No2010-06-252030-06-25Us
US8791122No2010-08-012030-08-01Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00434 mg/mLALOGPS
logP4.4ALOGPS
logP3.76ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)1.41ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area101.49 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity136.81 m3·mol-1ChemAxon
Polarizability54.98 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as dialkylarylamines. These are aliphatic aromatic amines in which the amino group is linked to two aliphatic chains and one aromatic group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Dialkylarylamines
Alternative Parents
Aminopyrazines / Imidolactams / Benzene and substituted derivatives / Organosulfonic acids and derivatives / Heteroaromatic compounds / Aminosulfonyl compounds / Dialkyl ethers / Carboxylic acids and derivatives / Azacyclic compounds / Organopnictogen compounds
show 3 more
Substituents
Dialkylarylamine / Aminopyrazine / Monocyclic benzene moiety / Pyrazine / Imidolactam / Benzenoid / Organic sulfonic acid or derivatives / Heteroaromatic compound / Organosulfonic acid or derivatives / Sulfonyl
show 14 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase.
Gene Name
PTGIR
Uniprot ID
P43119
Uniprot Name
Prostacyclin receptor
Molecular Weight
40955.485 Da
References
  1. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, Mukai H: Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag. Am J Cardiovasc Drugs. 2015 Jun;15(3):195-203. doi: 10.1007/s40256-015-0117-4. [PubMed:25850750]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Selexipag FDA Label [File]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on December 23, 2015 11:28 / Updated on September 23, 2018 19:37