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| Targets |
Ralinepag is a potent and selective agonist of the prostacyclin (IP) receptor. It exhibits a high affinity for this receptor, which is a G protein-coupled receptor that plays a crucial role in vascular homeostasis. Activation of the IP receptor leads to an increase in intracellular cyclic adenosine monophosphate (cAMP), which in turn causes potent vasodilation and inhibits platelet aggregation. Ralinepag shows significant species selectivity, with an EC50 of 8.5 nM for the human IP receptor and 530 nM for the rat IP receptor. It also shows some activity at the human DP1 receptor with an EC50 of 850 nM. This receptor binding profile underpins its therapeutic potential in conditions like PAH.
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| ln Vitro |
With EC50 values of 8.5 nM, 530 nM, and 850 nM for human and rat IP receptors and human DP1 receptors, respectively, ralinepag is a strong non-prostacyclin receptor agonist. With Kis of 1.2 nM, 3 nM, 76 nM, and 256 nM for monkey, human, rat, and dog IP receptors (ligand, [3H]-iloprost), and 2.6 μM, 9.6 μM, 610 nM, 143 nM, and 678 nM for human DP1, EP1, EP2, EP3v6, and EP4 receptors (ligand, [3H]-PGE2), respectively, Ralinepag (5c) exhibits a strong affinity for prostaglandin receptors. Ralinepag also did not affect the functional activity of the hERG channel (IC50 > 30 μM) or the cytochrome P450 enzymes (IC50 > 50 μM for CYP 1A2, 2D6, 3A4, 2C8, 2C9, and 2C19) in patch clamp experiments. With an IC50 of 38 nM, ralinepag also prevents human platelet aggregation triggered by ADP [1].
In vitro, Ralinepag demonstrates potent and selective agonist activity at the prostacyclin (IP) receptor. It displays strong binding affinity for prostaglandin receptors, with Ki values of 1.2 nM, 3 nM, and 76 nM for monkey, human, and rat IP receptors, respectively. Importantly, Ralinepag shows no significant functional activity at the hERG channel (IC50 > 30 µM) or on major cytochrome P450 enzymes (IC50 > 50 µM for CYPs 1A2, 2D6, 3A4, 2C8, 2C9, and 2C19), indicating a favorable safety profile regarding cardiac and metabolic drug interactions. Furthermore, Ralinepag effectively inhibits ADP-induced human platelet aggregation, with an IC50 of 38 nM. |
| ln Vivo |
In rats, monocrotaline (MCT)-induced elevations in pulmonary artery pressure and pulmonary vascular wall thickness can be considerably attenuated by ralingepag (30 mg/kg, orally) [1].
In vivo, Ralinepag has demonstrated significant efficacy in a rat model of pulmonary arterial hypertension. In studies using monocrotaline (MCT)-induced PAH in rats, oral administration of Ralinepag at a dose of 30 mg/kg substantially attenuated the increases in pulmonary artery pressure and pulmonary vascular wall thickness. These findings confirm its in vivo activity as a potent vasodilator and support its development for the treatment of PAH, where it has been shown to improve exercise capacity and reduce the risk of clinical worsening in patients. |
| Enzyme Assay |
The in vitro receptor binding affinity is typically determined using radioligand binding assays. In these experiments, membrane preparations from cells expressing the target receptor (e.g., IP receptor) are incubated with a radiolabeled ligand, such as [3H]-iloprost or [3H]-PGE2, in the presence of varying concentrations of Ralinepag. The amount of bound radioactivity is measured to calculate the inhibition constant (Ki), which quantifies the compound's affinity for the receptor. This cell-free system allows for the precise characterization of receptor-ligand interactions.
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| Cell Assay |
For cellular assays, the functional activity of Ralinepag as an IP receptor agonist is often assessed by measuring its ability to increase intracellular cAMP levels. Cells expressing the human IP receptor are treated with various concentrations of Ralinepag, and the subsequent accumulation of cAMP is quantified. The concentration required to achieve 50% of the maximal response (EC50) is then determined. Additionally, its effect on platelet function can be evaluated by measuring the inhibition of ADP-induced platelet aggregation in vitro.
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| Animal Protocol |
In the standard in vivo model for PAH, Sprague-Dawley rats are administered a single dose of monocrotaline (MCT) to induce pulmonary hypertension. After the disease is established, Ralinepag is administered orally, typically at a dose of 30 mg/kg. The primary endpoints measured are the reduction in pulmonary artery pressure and the decrease in pulmonary vascular wall thickness, which are assessed via right heart catheterization and histopathological examination of lung tissues, respectively.
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| ADME/Pharmacokinetics |
Ralinepag is an orally bioavailable compound, making it suitable for convenient, once- or twice-daily dosing. In a preclinical study, it was administered orally at 30 mg/kg. Its physicochemical properties include a LogP of 5, indicating high lipophilicity, which is typical for many receptor agonists. The compound is soluble in DMSO (55 mg/mL). Ralinepag is currently being studied in clinical trials for the treatment of pulmonary hypertension.
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| Toxicity/Toxicokinetics |
Based on its in vitro profile, Ralinepag demonstrates a favorable safety profile. In patch clamp experiments, it showed no effect on the hERG channel (IC50 > 30 µM), suggesting a low risk of QT prolongation. Similarly, it showed no significant inhibition of major CYP450 enzymes (IC50 > 50 µM), indicating a low potential for drug-drug interactions via this pathway. These findings are crucial for its development as a safe therapeutic agent.
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| References | |
| Additional Infomation |
Ralinepag is currently being used in clinical trials investigating the treatment of pulmonary hypertension.
Drug Indications Treatment of pulmonary hypertension Ralinepag is a novel, non-prostanoid prostacyclin receptor agonist currently in clinical development for the treatment of pulmonary arterial hypertension (PAH). Its discovery and development are detailed in the literature, highlighting its potential as an orally active agent for this serious condition. By improving exercise capacity and reducing the risk of clinical worsening in PAH patients, Ralinepag represents a promising new therapeutic option in a disease area with significant unmet medical need. |
| Molecular Formula |
C23H26CLNO5
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| Molecular Weight |
431.909245967865
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| Exact Mass |
431.15
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| CAS # |
1187856-49-0
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| Related CAS # |
1187856-49-0;1187857-75-5 (sodium);
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| PubChem CID |
44219292
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
609.1±35.0 °C at 760 mmHg
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| Flash Point |
322.2±25.9 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.582
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| LogP |
5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
538
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(O)(=O)COC[C@@H]1CC[C@@H](COC(N(C2=CC=C(Cl)C=C2)C2=CC=CC=C2)=O)CC1
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| InChi Key |
NPDKXVKJRHPDQT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H26ClNO5/c24-19-10-12-21(13-11-19)25(20-4-2-1-3-5-20)23(28)30-15-18-8-6-17(7-9-18)14-29-16-22(26)27/h1-5,10-13,17-18H,6-9,14-16H2,(H,26,27)
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| Chemical Name |
2-[[4-[[(4-chlorophenyl)-phenylcarbamoyl]oxymethyl]cyclohexyl]methoxy]acetic acid
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| Synonyms |
APD811; APD 811; APD-811
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~231.53 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.79 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 (5.79 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.79 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3153 mL | 11.5765 mL | 23.1530 mL | |
| 5 mM | 0.4631 mL | 2.3153 mL | 4.6306 mL | |
| 10 mM | 0.2315 mL | 1.1576 mL | 2.3153 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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