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Identification
Name Treprostinil
Accession Number DB00374 (APRD01272)
Type small molecule
Groups approved
Description

Treprostinil is a synthetic analogue of prostacyclin, used to treat pulmonary hypertension. Treprostinil is marketed as Remodulin®. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • treprostinil
Brand names
  • Remodulin
  • Viveta
Brand name mixtures Not Available
Categories
  • Antithrombotic Agents
  • Antihypertensive Agents
  • Vitamin K antagonists
CAS number 81846-19-7
Weight Average: 390.5131
Monoisotopic: 390.240624198
Chemical Formula C23H34O5
InChI Key InChIKey=PAJMKGZZBBTTOY-YRIDSSQKSA-N
InChI
InChI=1S/C23H34O5/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/h5-6,8,16-19,21,24-25H,2-4,7,9-14H2,1H3,(H,26,27)/t16-,17-,18+,19-,21+/m1/s1
Plain Text
IUPAC Name
2-{[(1S,2S,3aR,9aR)-2-hydroxy-1-[(3R)-3-hydroxyoctyl]-1H,2H,3H,3aH,4H,9H,9aH-cyclopenta[b]naphthalen-5-yl]oxy}acetic acid
SMILES
[H][C@@]12C[C@H](O)[C@@H](CC[C@H](O)CCCCC)[C@]1([H])CC1=C(C2)C(OCC(O)=O)=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Naphthalenes
  • Phenoxyacetates
Substructures
  • Hydroxy Compounds
  • Naphthalenes
  • Acetates
  • Phenols and Derivatives
  • Phenoxyacetates
  • Short-chain Hydroxy Acids
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Aromatic compounds
  • Anisoles
  • Alcohols and Polyols
  • Cyclohexenes and Derivatives
  • Phenyl Esters
Pharmacology
Indication For use as a continuous subcutaneous infusion or intravenous infusion (for those not able to tolerate a subcutaneous infusion) for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise.
Pharmacodynamics 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.
Mechanism of action The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In addition to treprostinil's direct vasodilatory effects, it also inhibits inflammatory cytokine. As a synthetic analogue of prostacyclin, it binds to the prostacyclin receptor, which subsequently induces the aforementioned downstream effects.
Absorption Relatively rapid and complete after subcutaneous infusion, with an absolute bioavailability approximately 100%. In patients with mild (n=4) or moderate (n=5) hepatic insufficiency and portopulmonary hypertension following a subcutaneous dose of 10 ng per kg of body weight per min for 150 mins the AUC 0-∞ was increased 3-fold and 5-fold respectively.
Volume of distribution
  • 14 L/70 kg
Protein binding Human plasma protein binding is approximately 91% in in vitro concentrations ranging from 330 to 10,000 µ/L.
Metabolism

Substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described (HU1 through HU5) however, the biological activity and metabolic fate of these are unknown. The chemical structure of HU1 is unknown. The metabolite HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Study results of in vitro human hepatic cytochrome P450 demonstrates that treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether treprostinil induces these enzymes has not been studied.
Route of elimination Not Available
Half life Terminal elimination half-life is approximately 2 to 4 hours. Plasma half-life is 34 and 85 minutes for intravenous and subcutaneous infusion of the drug, respectively.
Clearance Not Available
Toxicity Symptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of treprostinil.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • United therapeutics corp
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Prices
Unit description Cost Unit
Remodulin 10 mg/ml vial 737.0 USD ml
Remodulin 5 mg/ml vial 368.5 USD ml
Tyvaso inhalation starter kit 185.8 USD ml
Remodulin 2.5 mg/ml vial 184.25 USD ml
Tyvaso 1.74 mg/2.9 ml solution 174.55 USD ml
Tyvaso inhalation refill kit 165.68 USD ml
Remodulin 1 mg/ml vial 73.7 USD ml
Patents
Country Patent Number Approved Expires
United States 6521212 1998-11-13 2018-11-13
United States 5153222 1994-10-06 2014-10-06
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Insoluble at 25°C PhysProp
logP 4.1 PhysProp
Predicted Properties
Property Value Source
water solubility 7.31e-03 g/l ALOGPS
logP 3.53 ALOGPS
logP 4.00 ChemAxon Molconvert
logS -4.73 ALOGPS
pKa 14.93 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 86.99 ChemAxon Molconvert
rotatable bond count 10 ChemAxon Molconvert
refractivity 108.00 ChemAxon Molconvert
polarizability 45.01 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
PubChem Compound 54786 Link_out
PubChem Substance 46504572 Link_out
ChemSpider 49475 Link_out
ChEBI 50861 Link_out
ChEMBL 50861 Link_out
Therapeutic Targets Database DAP001214 Link_out
PharmGKB PA10217 Link_out
Drug Product Database 2246552 Link_out
RxList http://www.rxlist.com/cgi/generic/remodulin.htm Link_out
Drugs.com http://www.drugs.com/cdi/treprostinil-inhalation-solution.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Treprostinil Link_out
ATC Codes
  • B01AC21
AHFS Codes
  • 24:12.92
PDB Entries Not Available
FDA label show (223.4 KB)
MSDS show (17.4 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Prostacyclin receptor

Pharmacological action: yes
Actions: agonist

Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase

Organism class: human
UniProt ID: P43119 Link_out
Gene: PTGIR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, Clapp LH: Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2010 Jul 9. Pubmed
  2. Sprague RS, Bowles EA, Hanson MS, DuFaux EA, Sridharan M, Adderley S, Ellsworth ML, Stephenson AH: Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes. Microcirculation. 2008 Jul;15(5):461-71. Pubmed
  3. Olschewski H, Rose F, Schermuly R, Ghofrani HA, Enke B, Olschewski A, Seeger W: Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther. 2004 May;102(2):139-53. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Peroxisome proliferator-activated receptor delta

Pharmacological action: yes
Actions: agonist

Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Decreases expression of NPC1L1 once activated by a ligand

Organism class: human
UniProt ID: Q03181 Link_out
Gene: PPARD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ali FY, Egan K, FitzGerald GA, Desvergne B, Wahli W, Bishop-Bailey D, Warner TD, Mitchell JA: Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol. 2006 Feb;34(2):242-6. Epub 2005 Oct 20. Pubmed

3. P2Y purinoceptor 12

Pharmacological action: yes
Actions: agonist

Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Involved in platelets aggregation

Organism class: human
UniProt ID: Q9H244 Link_out
Gene: P2RY12 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:03

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.