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Details

Stereochemistry ABSOLUTE
Molecular Formula C23H34O5.C4H11NO2
Molecular Weight 495.6497
Optical Activity UNSPECIFIED
Defined Stereocenters 5 / 5
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TREPROSTINIL DIOLAMINE

SMILES

CCCCC[C@@]([H])(CC[C@]1([H])[C@@]2([H])Cc3cccc(c3C[C@@]2([H])C[C@@]1([H])O)OCC(=O)O)O.C(CO)NCCO

InChI

InChIKey=RHWRWEUCEXUUAV-ZSESPEEFSA-N
InChI=1S/C23H34O5.C4H11NO2/c1-2-3-4-7-17(24)9-10-18-19-11-15-6-5-8-22(28-14-23(26)27)20(15)12-16(19)13-21(18)25;6-3-1-5-2-4-7/h5-6,8,16-19,21,24-25H,2-4,7,9-14H2,1H3,(H,26,27);5-7H,1-4H2/t16-,17-,18+,19-,21+;/m0./s1

HIDE SMILES / InChI

Molecular Formula C23H34O5
Molecular Weight 390.5139
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 5 / 5
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula C4H11NO2
Molecular Weight 105.1358
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment:: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515411/

Treprostinil (marketed under the trade names Remodulin for infusion) is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure. Treprostinil is a potent oral antiplatelet agent. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed. Treprostinil had high affinity for the Prostaglandin D2 receptor (DP1), Prostaglandin E2 receptor EP2 subtype (EP2) and Prostaglandin D2 receptor (IP) receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, Prostaglandin F (FP) and thromboxane (TP) receptors. Treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Originator

Curator's Comment:: By 1976, Vane and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthetic molecule which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogs.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
REMODULIN

Approved Use

Remodulin is a prostacyclin vasodilator indicated for: Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) (1.1) Patients who require transition from Flolan®, to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. (1.2) 1.1 Pulmonary Arterial Hypertension Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) [see Clinical Studies (14.1)

Launch Date

1021939200000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
0.71 ng/mL
0.5 mg 3 times / day multiple, oral
dose: 0.5 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
0.54 ng/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
6.53 ng × h/mL
0.5 mg 3 times / day multiple, oral
dose: 0.5 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
2.46 ng × h/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
1.34 h
0.5 mg 3 times / day multiple, oral
dose: 0.5 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
1.06 h
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TREPROSTINIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
9%
TREPROSTINIL plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
20 mg 3 times / day steady, subcutaneous
Overdose
Dose: 20 mg, 3 times / day
Route: subcutaneous
Route: steady
Dose: 20 mg, 3 times / day
Sources:
unhealthy, 10 years
Health Status: unhealthy
Age Group: 10 years
Sex: F
Sources:
Disc. AE: Nausea, Blurred vision...
AEs leading to
discontinuation/dose reduction:
Nausea (1 patient)
Blurred vision (1 patient)
Sources:
7.5 mg single, subcutaneous
Overdose
Dose: 7.5 mg
Route: subcutaneous
Route: single
Dose: 7.5 mg
Sources:
unhealthy, 29 years
Health Status: unhealthy
Age Group: 29 years
Sex: F
Sources:
Disc. AE: Circulatory collapse...
AEs leading to
discontinuation/dose reduction:
Circulatory collapse (1 patient)
Sources:
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Sources:
Other AEs: Cough, Throat irritation...
Other AEs:
Cough (26 patients)
Throat irritation (26 patients)
Sources:
100 mg single, subcutaneous
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
unhealthy, 58 years
Health Status: unhealthy
Age Group: 58 years
Sex: F
Sources:
Disc. AE: Hypotension, Tachycardia...
AEs leading to
discontinuation/dose reduction:
Hypotension (1 patient)
Tachycardia (1 patient)
Arrhythmia ventricular (1 patient)
Dyspnea (1 patient)
Sources:
36 ug 4 times / day steady, respiratory
Recommended
Dose: 36 ug, 4 times / day
Route: respiratory
Route: steady
Dose: 36 ug, 4 times / day
Sources:
unhealthy, 7.1 - 19.2 years
Health Status: unhealthy
Age Group: 7.1 - 19.2 years
Sex: M+F
Sources:
Disc. AE: Bronchospasm...
AEs leading to
discontinuation/dose reduction:
Bronchospasm (3 patients)
Sources:
AEs

AEs

AESignificanceDosePopulation
Blurred vision 1 patient
Disc. AE
20 mg 3 times / day steady, subcutaneous
Overdose
Dose: 20 mg, 3 times / day
Route: subcutaneous
Route: steady
Dose: 20 mg, 3 times / day
Sources:
unhealthy, 10 years
Health Status: unhealthy
Age Group: 10 years
Sex: F
Sources:
Nausea 1 patient
Disc. AE
20 mg 3 times / day steady, subcutaneous
Overdose
Dose: 20 mg, 3 times / day
Route: subcutaneous
Route: steady
Dose: 20 mg, 3 times / day
Sources:
unhealthy, 10 years
Health Status: unhealthy
Age Group: 10 years
Sex: F
Sources:
Circulatory collapse 1 patient
Disc. AE
7.5 mg single, subcutaneous
Overdose
Dose: 7.5 mg
Route: subcutaneous
Route: single
Dose: 7.5 mg
Sources:
unhealthy, 29 years
Health Status: unhealthy
Age Group: 29 years
Sex: F
Sources:
Cough 26 patients
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Sources:
Throat irritation 26 patients
150 ug single, respiratory
Highest studied dose
Dose: 150 ug
Route: respiratory
Route: single
Dose: 150 ug
Sources:
healthy, 30.3 years
Health Status: healthy
Age Group: 30.3 years
Sex: M+F
Sources:
Arrhythmia ventricular 1 patient
Disc. AE
100 mg single, subcutaneous
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
unhealthy, 58 years
Health Status: unhealthy
Age Group: 58 years
Sex: F
Sources:
Dyspnea 1 patient
Disc. AE
100 mg single, subcutaneous
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
unhealthy, 58 years
Health Status: unhealthy
Age Group: 58 years
Sex: F
Sources:
Hypotension 1 patient
Disc. AE
100 mg single, subcutaneous
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
unhealthy, 58 years
Health Status: unhealthy
Age Group: 58 years
Sex: F
Sources:
Tachycardia 1 patient
Disc. AE
100 mg single, subcutaneous
Overdose
Dose: 100 mg
Route: subcutaneous
Route: single
Dose: 100 mg
Sources:
unhealthy, 58 years
Health Status: unhealthy
Age Group: 58 years
Sex: F
Sources:
Bronchospasm 3 patients
Disc. AE
36 ug 4 times / day steady, respiratory
Recommended
Dose: 36 ug, 4 times / day
Route: respiratory
Route: steady
Dose: 36 ug, 4 times / day
Sources:
unhealthy, 7.1 - 19.2 years
Health Status: unhealthy
Age Group: 7.1 - 19.2 years
Sex: M+F
Sources:
Overview

OverviewOther

Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: Treprostinil plasma AUC and Cmax increased approximately 2-fold when administered with gemfibrozil; Treprostinil AUC decreased by 30% when adminsitered with rifampin;
Page: 12,14
minor
weak (co-administration study)
Comment: Treprostinil AUC decreased approximately 14%, no effect on Cmax when adminstered with fluconazole;
Page: 12,14
no
no
no
no
no
no
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Treprostinil sodium Pharmacia.
2002 Apr
Gateways to clinical trials.
2002 Dec
Stability and preservative effectiveness of treprostinil sodium after dilution in common intravenous diluents.
2003 May 1
Gateways to clinical trials.
2003 Sep
Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers.
2004 Aug
Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion.
2004 Jan
Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion.
2004 May
Gateways to clinical trials.
2005 Dec
Gateways to clinical trials.
2005 Jun
Gateways to clinical trials.
2005 Sep
[The best of clinical cardiovascular pharmacology in 2005].
2006 Jan
Gateways to clinical trials.
2006 Jan-Feb
The prostacyclin analog, treprostinil sodium, provides symptom relief in severe Buerger's disease--a case report and review of literature.
2006 Jan-Feb
Gateways to clinical trials.
2006 Jul-Aug
Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension.
2006 Jun
Gateways to clinical trials.
2006 Mar
Treprostinil sodium (Remodulin), a prostacyclin analog, in the treatment of critical limb ischemia: open-label study.
2006 May-Jun
Gateways to clinical trials.
2006 Sep
Primary pulmonary hypertension as a manifestation of adult multi-system mitochondrial disorder.
2009 Apr 30
Gateways to clinical trials.
2009 Sep
Inhaled treprostinil and pulmonary arterial hypertension.
2010 Dec 3
Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis.
2010 Jan 29
Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo.
2010 Jul 23
Stability and antimicrobial effectiveness of treprostinil sodium in Sterile Diluent for Flolan.
2010 Jun
Gateways to clinical trials.
2010 May
Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial.
2010 May 4
The Adult Patient with Eisenmenger Syndrome: A Medical Update after Dana Point Part II: Medical Treatment - Study Results.
2010 Nov
Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist.
2012 Jul 1
Patents

Sample Use Guides

In Vivo Use Guide
Curator's Comment:: Treprostinil is available in three different formulations and four different routes of administration: Remodulin® (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso® (treprostinil sodium, inhaled administration), and Orenitram® (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH).
1.25 ng/kg/min (initial dose for continuous infusion, dosage should be chronically adjusted depending on clinical response)
Route of Administration: Other
In Vitro Use Guide
Curator's Comment:: Treprostinil (0.15 - 15 ng/ml) slightly increased contractile dynamics of cardiomyocytes at clinically relevant concentrations.
Treprostinil (0.15 - 15 ng/ml) rat cardiomyocytes
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:28:00 UTC 2021
Edited
by admin
on Fri Jun 25 21:28:00 UTC 2021
Record UNII
H1FKG90039
Record Status Validated (UNII)
Record Version
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Name Type Language
TREPROSTINIL DIOLAMINE
USAN  
USAN  
Official Name English
TREPROSTINIL DIETHANOLAMINE
Common Name English
2-((1R,2R,3AS,9AS)-2-HYDROXY-1-(3(S)-HYDROXYOCTYL)-2,3,3A,4,9,9A-HEXAHYDRO-1H-CYCLOPENTA(B)NAPHTHALEN-5-YLOXY)ACETIC ACID DIETHANOLAMINE SALT
Common Name English
TREPROSTINIL DIOLAMIN [WHO-DD]
Common Name English
TREPROSTINIL DIOLAMINE [ORANGE BOOK]
Common Name English
TREPROSTINIL DIOLAMIN
WHO-DD  
Common Name English
ACETIC ACID, 2-(((1R,2R,3AS,9AS)-2,3,3A,4,9,9A-HEXAHYDRO-2-HYDROXY-1-((3S)-3-HYDROXYOCTYL)-1H-BENZ(F)INDEN-5-YL)OXY)-, COMPD. WITH 2,2'-IMINOBIS(ETHANOL) (1:1)
Common Name English
UT-15C
Code English
TREPROSTINIL DIOLAMINE [USAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C78568
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
NCI_THESAURUS C29707
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
EU-Orphan Drug EU/3/05/310
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
Code System Code Type Description
EVMPD
SUB75907
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
ChEMBL
CHEMBL1237119
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
DRUG BANK
DBSALT001333
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
FDA UNII
H1FKG90039
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
NCI_THESAURUS
C152730
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
PUBCHEM
11179459
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
RXCUI
1927409
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
EPA CompTox
830354-48-8
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
CAS
830354-48-8
Created by admin on Fri Jun 25 21:28:00 UTC 2021 , Edited by admin on Fri Jun 25 21:28:00 UTC 2021
PRIMARY
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ACTIVE MOIETY