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Treprostinil sodium (LRX-15; Remodulin for infusion, Orenitram for oral, and Tyvaso for inhalation), a synthetic analog of prostacyclin (PGI2), is a novel and potent DP1 and EP2 agonist with EC50 values of 0.6±0.1 and 6.2±1.2 nM, respectively. Treprostinil is a vasodilator that is applied to the management of hypertension in the lungs. The FDA approved treprostinil inhalation form in July 2009; it is sold under the trade name Tyvaso.
Physicochemical Properties
| Molecular Formula | C23H33NAO5 |
| Molecular Weight | 412.4949 |
| Exact Mass | 412.22 |
| Elemental Analysis | C, 66.97; H, 8.06; Na, 5.57; O, 19.39 |
| CAS # | 289480-64-4 |
| Related CAS # | Treprostinil;81846-19-7; Treprostinil diethanolamine; 830354-48-8 |
| PubChem CID | 23663413 |
| Appearance | White to off-white solid powder |
| Density | 587.1ºC at 760 mmHg |
| Boiling Point | 587.1ºC at 760 mmHg |
| Flash Point | 199.3ºC |
| Vapour Pressure | 1.25E-14mmHg at 25°C |
| LogP | 3.583 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 29 |
| Complexity | 502 |
| Defined Atom Stereocenter Count | 5 |
| SMILES | [Na+].O([H])C1([H])C([H])([H])[C@]2([H])C([H])([H])C3C(=C([H])C([H])=C([H])C=3C([H])([H])[C@@]2([H])C1([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])O[H])OC([H])([H])C(=O)[O-] |
| InChi Key | IQKAWAUTOKVMLE-ZSESPEEFSA-M |
| InChi Code | InChI=1S/C23H34O5.Na/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);/q;+1/p-1/t16-,17-,18+,19-,21+;/m0./s1 |
| Chemical Name | sodium;2-[[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[g]naphthalen-5-yl]oxy]acetate |
| Synonyms | UT-15; LRX 15 sodium; UT 15; LRX15 sodium; UT15; LRX-15 sodium; BW 15AU sodium; U-62840 sodium; Uniprost; Treprostinil; Orenitram; Remodulin; Treprostinil (sodium); 7JZ75N2NT6; TREPROSTINIL SODIUM SALT; CHEBI:50863; sodium;2-[[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[g]naphthalen-5-yl]oxy]acetate; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
IP Receptor ( EC50 = 1.9 nM ); TP Receptor ( EC50 = 919 nM ); IP Receptor ( Ki = 32.1 nM ); FP Receptor ( Ki = 4680 nM ); DP1 ( EC50 = 0.6±0.1 nM ); EP2 ( EC50 = 6.2±1.2 nM ); DP1 ( EC50 = 4.4 nM ); EP2 ( EC50 = 3.6 nM ); EP4 ( EC50 = 826 nM ); EP3 ( EC50 = 2505 nM ); EP1 ( Ki = 212 nM ); EP1 ( EC50 = 285 nM ); EP3 ( EC50 = 68.9 nM ); EP4 ( EC50 = 181 nM ) - Prostacyclin receptor (IP)：Treprostinil acts as a potent agonist with a Ki value of 0.3 nM. [1] - Prostaglandin DP1 receptor (DP1)：Treprostinil exhibits high agonist activity with a Ki value of 0.14 nM. [1] - Prostaglandin EP2 receptor (EP2)：Treprostinil is a potent agonist with a Ki value of 0.7 nM. [1] |
| ln Vitro |
Treprostinil sodium exhibits low affinity for EP1 and EP4 receptors, even lower affinity for EP3, FP, and TP receptors, and high affinity for DP1, EP2, and IP receptors (Ki=4.4, 3.6, and 32 nM, respectively). Similar to treprostinil, activation of IP, DP1, and EP2 receptors can all cause the human pulmonary arteries to vasodilate[1]. Cultured endothelial colony forming cells' viability is inhibited by treprostinil sodium. The proliferation of endothelial colony forming cells is induced by conditioned media derived from mesenchymal stem cells that have been treated with treprostinil[5]. - Receptor binding and activation： - Treprostinil demonstrates nanomolar affinity for IP, DP1, and EP2 receptors, with the highest potency at DP1 (Ki = 0.14 nM). It activates these receptors to induce cAMP production, leading to vasodilation and anti-proliferative effects. [1] - VEGF-A induction in mesenchymal stem cells (MSCs)： - Treprostinil (10–100 nM) significantly increases VEGF-A secretion in MSCs via activation of IP and DP1 receptors. This effect is blocked by specific antagonists, confirming receptor-mediated signaling. [2] |
| ln Vivo |
The most recent medication to be approved by the FDA to treat pulmonary arterial hypertension (PAH), a deadly orphan disease, is inhaled treprostinil sodium, a prostacyclin analog[2]. Compared to a placebo, treprostinil lessens platelet deposition early after transplantation and maintains the sinusoidal endothelial cell lining. The treprostinil group maintains blood flow close to normal levels, while the placebo group's hepatic tissue blood flow is significantly reduced[3]. In Matrigel implanted in nude mice, treprostinil treatment dramatically increases the vessel-forming ability of endothelial colony forming cells combined with mesenchymal stem cells. Treprostinil's pro-angiogenic effect is also inhibited by silencing the VEGF-A gene in mesenchymal stem cells[4]. Hematopoietic stem and progenitor cells from mice and humans respond best to treprostinil when it comes to increasing intracellular cAMP levels[5]. When compared to normoxic mice, treatment with Treprostinil significantly reduces the recruitment of cells. Treprostinil fails to reverse right ventricular hypertrophy, but it does lower right ventricular systolic pressure and slightly lessen vascular remodelling[6]. - Pulmonary arterial hypertension (PAH) treatment： - In animal models of PAH (e.g., chronic hypoxia-induced rats), Treprostinil administered via inhalation or subcutaneous infusion reduces pulmonary vascular resistance and improves right ventricular function. The therapeutic effect is attributed to its dual activation of IP and DP1 receptors, leading to vasodilation and inhibition of fibrocyte recruitment. [3][6] - Ischemia-reperfusion injury protection： - In rat orthotopic liver transplantation models, Treprostinil (10–50 ng/kg/min, intravenous) reduces hepatic injury by suppressing oxidative stress and neutrophil infiltration. This effect is associated with increased endothelial nitric oxide synthase (eNOS) activity and reduced pro-inflammatory cytokine release. [5] - Enhanced hematopoietic progenitor cell transplantation： - In murine models, Treprostinil (0.1–1 mg/kg, intraperitoneal) improves engraftment of hematopoietic stem cells by promoting their migration to bone marrow. This is mediated by upregulation of CXCR4 chemokine receptor expression on progenitor cells. [4] |
| Enzyme Assay |
- Prostanoid receptor binding assay：
1. Membrane preparations from HEK293 cells transfected with human IP, DP1, or EP2 receptors are incubated with radiolabeled ligands (e.g., [³H]-iloprost for IP) in the presence of Treprostinil (0.01–100 nM).
2. Bound and free ligands are separated by filtration, and radioactivity is measured to determine Ki values. Treprostinil displaces [³H]-iloprost with high potency at IP (Ki = 0.3 nM) and DP1 (Ki = 0.14 nM). [1] |
| Cell Assay |
Hematopoietic stem and progenitor cells from humans or mice are cultured for one hour and twenty-four hours at 37°C either in the presence of vehicle or in combination with 10 μM Treprostinil and 30 μM forskolin. The apoptosis kit is used to stain cells for externalized phosphatidylserine after they have been washed with phosphate-buffered saline at 4°C[5]. - VEGF-A secretion in MSCs： 1. MSCs are treated with Treprostinil (10–100 nM) for 24 hours in serum-free medium. 2. Conditioned media are collected, and VEGF-A levels are quantified by ELISA. Treprostinil increases VEGF-A secretion in a concentration-dependent manner (EC50 ≈ 50 nM). [2] - Endothelial colony forming cell (ECFC) angiogenesis assay： 1. ECFCs are co-cultured with Treprostinil-treated MSCs in Matrigel. 2. Tube formation is assessed after 12 hours. Treprostinil enhances ECFC angiogenic sprouting by 2–3-fold compared to controls, dependent on VEGF-A secretion from MSCs. [2] |
| Animal Protocol |
Rats: For the study, male Lewis rats weighing between 200 and 300 g are employed. 24 hours prior to hepatectomy, donor animals are given treprostinil or a placebo, and the corresponding recipient animal receives the same care until the moment of sacrifice. Treatment is invisible to the surgeon. To study what happens right after IRI, recipients are sacrificed 1, 3, 6, 24 and 48 hours after transplantation. Using an Alzet implantable osmotic pump, subcutaneous administration of treprostinil (100 ng/kg/min) or placebo is performed. This dosage is chosen to produce a plasma concentration that is steady-state and falls between 5 and 20 ng/mL[3]. Mice: Mice that have had bone marrow transplantation (BMT) are split up into five groups, each with six to ten mice. In a normobaric chamber, one group of mice is exposed to hypoxia (10% inspired oxygen fraction), while the other group of mice (control BMT) spends 28 days in a normoxic chamber with a normal oxygen environment (21% inspired O2 fraction). While the two other groups of mice receive four weeks of hypoxic exposure and receive Treprostinil infusions at varying dose levels (14 ng/kg and 70 ng/kg per minute), the sham group mice receive saline treatment. Comparatively, infusion rates for humans in PAH therapy range from 10 to 60 ng/kg per minute[6]. - Chronic hypoxic PAH model： 1. Rats are exposed to hypoxia (10% O₂) for 4 weeks to induce PAH. 2. Treprostinil is administered via subcutaneous osmotic pumps (10–50 ng/kg/min) or inhaled aerosol (1–5 μg/kg) daily for 2 weeks. 3. Pulmonary hemodynamics are measured via right heart catheterization, and lung tissues are analyzed for fibrocyte infiltration (CD45⁺/collagen I⁺ cells). [6] - Liver transplantation model： 1. Rats undergo orthotopic liver transplantation with 60-minute warm ischemia. 2. Treprostinil (10–50 ng/kg/min) is infused intravenously starting 30 minutes before reperfusion and continuing for 6 hours postoperatively. 3. Liver function is assessed by serum alanine aminotransferase (ALT) levels, and histological damage is evaluated by hematoxylin-eosin staining. [5] |
| ADME/Pharmacokinetics |
- Subcutaneous/intravenous administration：
- Treprostinil is rapidly absorbed with a bioavailability of ~90%. Plasma protein binding is ~90%, primarily to albumin. The terminal half-life is 3–4 hours, and elimination occurs via hepatic metabolism (CYP3A4-mediated oxidation) and renal excretion. [3] - Inhaled administration： - Inhaled Treprostinil achieves peak plasma concentrations within 10–15 minutes, with a bioavailability of ~20–30%. The inhaled route reduces systemic exposure compared to parenteral administration, minimizing off-target effects. [3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation One patient taking treprostinil breastfed her infant for one year without any complications. However, until more data are available, treprostinil should only be used with careful monitoring during breastfeeding. ◉ Effects in Breastfed Infants A woman developed pulmonary artery hypertension and was treated with intravenous treprostinil beginning at 32 weeks of gestation and titrated up to 26 ng/kg/min. The dose was nearly doubled postpartum because of worsening symptoms. She breastfed (extent not stated) her infant for one year with no apparent drug-related problems, although there was concern for obesity at 6 months of age. The infant was healthy and developing normally at 2 years of age. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. - Side effects： - Common adverse effects include headache, flushing, and jaw pain, attributed to vasodilation. At higher doses, Treprostinil may cause hypotension, nausea, and diarrhea. [3] - Plasma protein binding： - Treprostinil is highly bound to plasma proteins (~90%), which may increase drug-drug interactions with other highly protein-bound compounds (e.g., warfarin). [3] |
| References |
[1]. Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist. Biochem Pharmacol. 2012 Jul 1;84(1):68-75. [2]. Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost. 2015 Oct;114(4):735-47. [3]. Inhaled treprostinil sodium for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2011 Nov;12(16):2583-93. [4]. Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation. Mol Pharmacol. 2016 Jun;89(6):630-44. [5]. Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. Am J Transplant. 2011 Nov;11(11):2508-16. [6]. Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension. Eur Respir J. 2010 Dec;36(6):1302-14. |
| Additional Infomation |
Treprostinil sodium is an organic sodium salt. It contains a treprostinil. Drug Indication Treatment of adult patients with WHO Functional Class (FC) III or IV and: inoperable chronic thromboembolic pulmonary hypertension (CTEPH), orpersistent or recurrent CTEPH after surgical treatmentto improve exercise capacity. Treatment of pulmonary arterial hypertension Treatment of chronic thromboembolic pulmonary hypertension - Mechanism of action： - Treprostinil exerts its therapeutic effects through dual activation of IP and DP1 receptors, leading to vasodilation, inhibition of platelet aggregation, and suppression of vascular remodeling. Its activation of EP2 receptors may also contribute to anti-inflammatory effects. [1][6] - Clinical use： - Approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Available in multiple formulations: subcutaneous/intravenous solution, inhaled aerosol, and oral tablets. [3] - FDA-approved indications： - Treprostinil is indicated for improving exercise capacity and delaying clinical worsening in patients with PAH. The inhaled formulation is specifically approved for patients with severe symptoms (WHO functional class III/IV). [3] |
Solubility Data
| Solubility (In Vitro) |
DMSO: 25~82 mg/mL (~198.8 mM) Water: 82 mg/mL Ethanol: 82 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 50 mg/mL (121.22 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4243 mL | 12.1215 mL | 24.2430 mL | |
| 5 mM | 0.4849 mL | 2.4243 mL | 4.8486 mL | |
| 10 mM | 0.2424 mL | 1.2122 mL | 2.4243 mL |