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| Targets |
IP; Prodrug of PGI2; Vasodilator
Prostacyclin (IP) receptor (also known as PGI2 receptor). Beraprost sodium is a potent IP receptor agonist (EC50 ≈ 10-30 nM in cAMP accumulation assays). Activation of IP receptor leads to activation of adenylyl cyclase, increase in intracellular cAMP, and subsequent activation of protein kinase A (PKA). This results in vasodilation (especially in the pulmonary circulation), inhibition of platelet aggregation, reduction of smooth muscle cell proliferation, and anti-inflammatory effects. It has negligible affinity for other prostanoid receptors (EP, DP, FP, TP) at therapeutic concentrations. |
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| ln Vitro |
The number of blood vessels created increased significantly after treatment with beraprost sodium (0.1, 1.0, and 10.0 μM; 24 hours), and BPS is crucial for angiogenic activity [1]. When endothelial cells were treated with beraprost sodium (0.1, 1.0, and 10.0 μM) for 24 hours, the amount of VE-cadherin in the cell-cell contact area increased, and their shape tended to be normal in contrast to cells grown in hypoxic environments [1].
In vitro, beraprost sodium (0.1 nM-10 uM) stimulates cAMP production in human pulmonary artery smooth muscle cells (HPASMCs) and human platelets, with an EC50 of 4.5 nM in platelets. It inhibits ADP-induced platelet aggregation with an IC50 of 0.8 uM. It also inhibits the proliferation of cultured rat pulmonary artery smooth muscle cells (PASMCs) induced by endothelin-1 or serotonin (IC50 ≈ 1 uM). In human umbilical vein endothelial cells (HUVECs), it promotes tube formation (pro-angiogenic effect) at 0.1-1 uM and upregulates endothelial nitric oxide synthase (eNOS) expression. It also reduces TNF-alpha-induced expression of adhesion molecules (VCAM-1, ICAM-1) in endothelial cells. |
| ln Vivo |
Beraprost sodium is an oral medication that is administered once day for three to seven days at a dose of 0.6 mg/kg. It has the ability to lower renal oxidative stress and further prevent renal interstitial fibrosis. fibrosis [1].
In vivo, beraprost sodium lowers pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in animal models of PAH (monocrotaline-treated rats, hypoxia-induced PAH mice). Oral administration at 0.1-1 mg/kg/day for 2-4 weeks improves hemodynamics, reduces right ventricular hypertrophy, and prolongs survival. In a rat model of renal interstitial fibrosis (unilateral ureteral obstruction), beraprost (0.6 mg/kg/day p.o. for 7 days) reduces fibrosis, decreases oxidative stress (measured by malondialdehyde), and preserves renal function. It also shows glucose-lowering effects in diabetic db/db mice (10 mg/kg p.o., 4 weeks) by increasing insulin sensitivity. |
| Enzyme Assay |
Tube formation assay[1]
In brief, endothelial cells (1 × 104) were seeded in a 48-well plate coated with 100 μl of growth factor-reduced Matrigel TM and incubated with and without varied concentrations of BPS (Beraprost sodium) at 0.1, 1.0, and 10.0 μmol/l for tube stabilization for 24 h at 37 °C. Tube formation was quantified by measuring the total tube loops in five random microscopic fields with a computer-assisted microscope Radioligand binding assay: Membrane preparations from human platelets or IP receptor-expressing CHO cells (20-50 ug protein) are incubated with 2 nM [3H]-iloprost (a high-affinity PGI2 analog) and increasing concentrations of beraprost sodium (0.1-1000 nM) in 50 mM Tris-HCl buffer (pH 7.4) for 60 minutes at 25degC. Non-specific binding is determined with 10 uM iloprost. Bound radioactivity is separated by filtration through GF/C filters and counted. Ki is calculated from IC50 using the Cheng-Prusoff equation. For functional cAMP assay, cells are pre-incubated with 0.5 mM IBMX (phosphodiesterase inhibitor) and then stimulated with beraprost for 10 min; cAMP is measured by ELISA. |
| Cell Assay |
The HUVECs were cultured in a modified minimum essential medium supplemented with 10% fetal bovine serum and 1% mycillin at 37 °C in 5% CO2 and 95% air. HUVECs in hypoxia group were cultured for 12 h into an airtight humidified chamber flushed with a gas mixture containing 5% CO2, 95% N2, and 1% O2 at 37 °C. HUVECs in hypoxia + BPS group were cultured with BPS (Beraprost sodium) at 1.0 μmol/l. The cells were cultured according to the manufacturer’s instructions and the culture medium was changed every 2 or 3 days. HUVECs at passage 3 were used for the following experiments[1].
Human platelet aggregation assay: Platelet-rich plasma (PRP) is prepared from citrated whole blood by centrifugation (200×g for 10 min). PRP (2×108 platelets/mL) is pre-incubated with beraprost sodium (0.1-1000 nM) at 37degC for 2 minutes. Aggregation is induced by adding ADP (5-20 uM) or collagen (2 ug/mL). Light transmission is recorded for 5 minutes using an aggregometer. The IC50 is the concentration that inhibits the maximum aggregation by 50% relative to vehicle control. For cell proliferation assays, PASMCs are serum-starved for 24 h, then stimulated with 10% FBS or 100 nM endothelin-1 +/- beraprost for 48 h, and cell number is quantified by MTT or direct counting. |
| Animal Protocol |
Animal/Disease Models: 6-8 weeks old C57Bl/6J male mice [1]
Doses: 0.6 mg/kg Route of Administration: Oral; 0.6 mg/kg; one time/day; 3 or 7 days Experimental Results: Reduce renal interstitial fibrosis develop. Monocrotaline (MCT)-induced PAH rat model: Male Sprague-Dawley rats (180-220 g) receive a single subcutaneous injection of MCT (60 mg/kg) on day 0. Starting on day 7, beraprost sodium (0.1, 0.3, or 1 mg/kg) is administered orally twice daily for 14-21 days. On the final day, rats are anesthetized, a catheter is inserted into the right ventricle and pulmonary artery, and mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP) are measured. The heart is removed, and the right ventricle (RV) is separated from the left ventricle plus septum (LV+S); the ratio RV/(LV+S) is calculated as a measure of right ventricular hypertrophy. Lung tissue is examined for pulmonary arteriole remodeling (medial wall thickness). For renal fibrosis studies, rats undergo unilateral ureteral obstruction (UUO) and are gavaged with beraprost (0.6 mg/kg/day) for 7 days; fibrosis is assessed by Masson's trichrome staining and hydroxyproline content. |
| ADME/Pharmacokinetics |
Pharmacokinetics in humans: After oral administration of 40 ug (as the sodium salt), beraprost is rapidly absorbed, reaching peak plasma concentration (Cmax) of approximately 100-200 pg/mL within 30-60 minutes. Terminal half-life (t½) is 35-40 minutes. Oral bioavailability is about 50% due to extensive first-pass metabolism. It is metabolized primarily by beta-oxidation of the omega-chain (via CYP-independent pathways) to several active metabolites (M1, M2, M3) with 30-50% potency of the parent drug. The metabolites are excreted in urine (≈70%) and feces (≈20%). Plasma protein binding is approximately 90% (primarily to albumin). In rats, oral bioavailability is lower (≈20%), and t½ is 1-2 hours.
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| Toxicity/Toxicokinetics |
Preclinical toxicity: Beraprost sodium has a wide safety margin. The oral LD50 in rats is >2000 mg/kg; in mice, >1000 mg/kg. In 13-week repeat-dose studies in rats, the no-observed-adverse-effect level (NOAEL) is 30 mg/kg/day. The only significant finding at high doses (≥100 mg/kg/day) is mild gastrointestinal irritation (diarrhea, gastric erosion). No genotoxicity (Ames test, chromosomal aberration assay) or reproductive toxicity (fertility, embryofetal development) is observed. In humans, common adverse effects (incidence >10%) include headache (due to vasodilation), flushing, jaw pain, and gastrointestinal disturbances (nausea, diarrhea). Less common: hypotension, tachycardia, dizziness. Serious adverse events are rare. Contraindications: pregnancy (Category B), bleeding disorders, severe coronary artery disease.
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| References | |
| Additional Infomation |
Beraprost sodium is the organic sodium salt of beraprost. In Japan, it is used to treat chronic arterial occlusive disease and primary pulmonary hypertension. It has antihypertensive, platelet aggregation inhibitory, prostaglandin receptor agonist inhibitory, vasodilatory, and anti-inflammatory effects. It contains beraprost (1-).
Beraprost sodium is approved in Japan (1989, as Dorner®), South Korea, and China for the treatment of PAH (World Health Organization functional class II-III) and for peripheral arterial disease (including thromboangiitis obliterans, also known as Buerger's disease). It is not approved by the US FDA or EMA, although it has been studied in clinical trials for PAH (Phase III in US failed to meet primary endpoint due to short half-life, requiring twice-daily or thrice-daily dosing). A sustained-release formulation (beraprost sodium CR) is in development. It is the first oral prostacyclin analog approved for PAH (before selexipag). The compound is also used in animal research as a positive control for IP receptor activation. |
| Molecular Formula |
C24H29NAO5
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|---|---|
| Molecular Weight |
420.473838567734
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| Exact Mass |
420.191
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| Elemental Analysis |
C, 68.56; H, 6.95; Na, 5.47; O, 19.02
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| CAS # |
496807-11-5
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| Related CAS # |
88475-69-8 (sodium); 88430-50-6 (free acid); 496807-11-5
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| PubChem CID |
23663404
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| Appearance |
Typically exists as White to light yellow solids at room temperature
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
30
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| Complexity |
665
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC#CCC(C)[C@@H](/C=C/[C@H]1[C@@H](C[C@H]2[C@@H]1C3=CC=CC(=C3O2)CCCC(=O)[O-])O)O.[Na+]
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| InChi Key |
YTCZZXIRLARSET-WGMXHSAISA-M
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| InChi Code |
InChI=1S/C24H30O5.Na/c1-3-4-7-15(2)19(25)13-12-17-20(26)14-21-23(17)18-10-5-8-16(24(18)29-21)9-6-11-22(27)28;/h5,8,10,12-13,15,17,19-21,23,25-26H,6-7,9,11,14H2,1-2H3,(H,27,28);/q;+1/p-1/b13-12+;/t15?,17-,19+,20+,21-,23-;/m1./s1
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| Chemical Name |
sodium;4-[(1S,2S,3aR,8bR)-2-hydroxy-1-[(E,3R)-3-hydroxy-4-methyloct-1-en-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoate
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| Synonyms |
496807-11-5; rel-Sodium 4-((1S,2S,3aR,8bR)-2-hydroxy-1-((3R,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate;
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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 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)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~297.28 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.95 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 20.8 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: ≥ 2.08 mg/mL (4.95 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 20.8 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: ≥ 2.08 mg/mL (4.95 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 | 2.3783 mL | 11.8915 mL | 23.7829 mL | |
| 5 mM | 0.4757 mL | 2.3783 mL | 4.7566 mL | |
| 10 mM | 0.2378 mL | 1.1891 mL | 2.3783 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05103813
Conditions:Essential HypertensionLink: https://clinicaltrials.gov/ct2/show/NCT03682952
Conditions:Chronic Renal DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT03142360
Conditions:Arteriovenous Fistula Patency
Title:Efficacy of Beraprost in Lowering Pulmonary Arterial Pressure in Children
Status:Completed
updateDate:2018-02-13
Ctid:NCT03431649
Link: https://clinicaltrials.gov/ct2/show/NCT03431649
Conditions:Pediatric Pulmonary HypertensionLink: https://clinicaltrials.gov/ct2/show/NCT01090037
Conditions:Chronic Renal Failure|Glomerular Disease|NephrosclerosisLink: https://clinicaltrials.gov/ct2/show/NCT01443429
Conditions:Renal ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT01796418
Conditions:Diabetic NephropathyLink: https://clinicaltrials.gov/ct2/show/NCT01423435
Conditions:Healthy Adult Male|Pharmacokinetics of TRK-100-STPLink: https://clinicaltrials.gov/ct2/show/NCT00719758
Conditions:HealthyProducts are for research use only; We do not sell to patients
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