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| Targets |
S1PR1 12.6-493 nM (EC50)
Targets S1P1 as a selective G-protein-biased agonist, with EC50 values ranging from 12.6 to 493 nM in S1P1-overexpressing cells and HUVECs. Unlike conventional S1P1 agonists that cause receptor internalization and lymphopenia, SAR247799 activates G-protein signaling without inducing significant receptor desensitization, which spares lymphocytes. |
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| ln Vitro |
In HUVECs, SAR247799 (0, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μM; 10 min) phosphorylates extracellular-regulated kinase-1/2 (Erk1/2) and protein kinase B (Akt) in a concentration-dependent manner[1]. In HUVECs, SAR247799 (0-10 μM, 8 min) causes an impedance shift in a dose-dependent way[1]. Ca2+ flow test results in no desensitization in S1P1 Chinese hamster ovary (CHO) cells when exposed to SAR247799 (1 μM, 1st)[1].
SAR247799 activates G-protein signaling pathways (Gi) downstream of S1P1 without promoting beta-arrestin recruitment or receptor internalization. This biased signaling profile results in endothelial cell protection (e.g., inhibition of vascular leakage, promotion of endothelial barrier integrity) while minimizing effects on lymphocyte trafficking, thereby avoiding immunosuppression. |
| ln Vivo |
The severity of acute kidney injury caused by ischemia/reperfusion (I/R) is dose-dependently reduced by SAR247799 (1 and 3 mg/kg; po; 1 h before renal occlusion)[1]. In pig models of coronary endothelial dysfunction, SAR247799 (0.3, 1, 3 mg/kg; iv) dose-dependently enhances the coronary conductance ratio[1]. Pigs' exposure (Cmax and AUC) to SAR247799 (30-min intravenous treatment; 8–10 week old farm pigs) rises with dose. Pharmacokinetic parameters[1]: Dose (mg/kg) N Cmax (g/mL) Tmax (h) Tlast (h) AUC0-last (gh/mL) Cl (L/h/kg) Vss (L/kg) T1/2z (h) 1 4 2.08 (8) 0.5 [0.5] [8-48] 11.8 (46) 0.113 (75) 0.516 (11) 5.62 (57) 3 7 8.10 (12) 0.5 [0.5] [24 -72] 42.2 (23) 0.0754 (30) 0.446 (16) 6.21 (28) 10 3 36.7 (5) 0.5 [0.5-0.75] 72 294 (13) 0.0343 (13) 0.338 (7) 7.73 (8) 30 6 112 (27) 0.5 [0.5-1.0] [48-72] 908 (16) 0.0338 (18) 0.294 (11) 7.35 (11) Mean values with (CV%) except Tmax, which is expressed as median value with [range]. Cmax stands for maximum concentration. Tmax, or the time at which concentration reaches its maximum. Tlast is the sampled last time point. Area under the curve from 0 to the last time point is called AUC0-last. Cl, clearing. Vss stands for volume in a steady state or distribution volume. Elimination half-life, T1/2z. N is the total number of creatures.
In vivo, SAR247799 (1 and 3 mg/kg, p.o.) administered 1 hour before renal occlusion protects renal proximal tubules against necrosis and blunts the development of interstitial hemorrhage in a renal ischemia-reperfusion injury model. It reduces serum creatinine (89% and 96% at 1 and 3 mg/kg) and urea (61% and 85% at 1 and 3 mg/kg). In pig studies, exposure (Cmax and AUC) increases with dose. A first-in-human trial has been completed. |
| Enzyme Assay |
Cell-free GTPgammaS binding assays are performed using membranes from S1P1-overexpressing HEK293 cells. Membranes (10 microg/well) are incubated with [3⁵S]GTPgammaS (0.1 nM), 10 microM GDP, and increasing SAR247799 concentrations (0.1 nM-10 microM) in assay buffer for 60 min at 30degC. Bound [3⁵S]GTPgammaS is separated by filtration through GF/B filters and counted to assess G-protein activation (EC50=12.6 nM in these cells).
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| Cell Assay |
HUVECs (Human Umbilical Vein Endothelial Cells) are grown in EGM-2 medium and used between passages 3-6. Cells are seeded in 96-well plates and grown to confluence. For barrier function assessment, cells are treated with SAR247799 (0.1 nM-10 microM) for 30 min, then stimulated with thrombin (1 U/mL) or histamine (100 microM). Endothelial barrier integrity is measured by transendothelial electrical resistance (TEER) using ECIS (electric cell-substrate impedance sensing) technology. EC50 ranges from 12.6 to 493 nM depending on assay.
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| Animal Protocol |
Animal/Disease Models: Acute kidney injury rats (12 to 15weeks old Fischer rats)[1]
Doses: 1 and 3 mg /kg Route of Administration: Po; administered 1 hour before renal occlusion. Experimental Results: Inhibited the increase in serum creatinine (89 and 96% at 1 and 3 mg/kg) and urea (61 and 85% at 1 and 3 mg/kg). Protected renal proximal tubules against necrosis and blunted the development of interstitial hemorrhage. Animal/Disease Models: Acute kidney injury rats (8- to 12weeks old Fischer rats)[1] Doses: 3 mg/kg Route of Administration: Po; twice a day for 7 days and twice a day for 7 day Experimental Results: demonstrated a dosedependent trend for reducing macrophage. In renal ischemia-reperfusion injury models, mice undergo unilateral or bilateral renal pedicle clamping for 30-45 min followed by reperfusion. SAR247799 (1-3 mg/kg) is administered orally 1 h before renal occlusion. Blood samples are collected at 24-48 h post-reperfusion for measurement of serum creatinine, blood urea nitrogen (BUN), and cytokine levels. Kidneys are harvested for histopathology (H&E staining) and TUNEL assay for apoptosis assessment. |
| ADME/Pharmacokinetics |
SAR247799 has been evaluated in a first-in-human, Phase 1 clinical study (NCT04065763) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses. Detailed PK parameters are not publicly available, but in pig studies, exposure (Cmax and AUC) increases with dose following 30-min intravenous administration at doses ranging from 0.1 to 3 mg/kg.
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| Toxicity/Toxicokinetics |
Phase 1 clinical trial data for SAR247799 (NCT04065763) includes safety assessment. As a G-protein-biased S1P1 agonist that spares lymphocytes, it is expected to have an improved safety profile compared to conventional S1P1 modulators that cause lymphopenia and associated infection risk. No first-dose bradycardia (fingolimod-like effect) was reported in limited data, but cardiovascular monitoring was still included.
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| References |
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| Additional Infomation |
SAR247799 is an investigational drug not yet approved for clinical use. It has completed Phase 1 clinical trials for endothelial protection in conditions including type-2 diabetes, metabolic syndrome, and vascular hyperpermeability. It represents a novel biased agonist approach to achieve S1P1-mediated therapeutic effects (endothelial protection) without undesirable immunosuppression (lymphopenia), offering a potential treatment for acute kidney injury and cardiovascular diseases.
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| Molecular Formula |
C21H16CLN3O5
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|---|---|
| Molecular Weight |
425.821844100952
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| Exact Mass |
425.077
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| CAS # |
1315311-14-8
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| PubChem CID |
53312127
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
587
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(O)(=O)COC1=C(C)C=C(C2=NC3=CN=C(OC4=CC=CC(Cl)=C4)N=C3O2)C=C1C
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| InChi Key |
WRBZNIUFAKIIQG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16ClN3O5/c1-11-6-13(7-12(2)18(11)28-10-17(26)27)19-24-16-9-23-21(25-20(16)30-19)29-15-5-3-4-14(22)8-15/h3-9H,10H2,1-2H3,(H,26,27)
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| Chemical Name |
2-[4-[5-(3-chlorophenoxy)-[1,3]oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy]acetic acid
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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: 33.33 mg/mL (78.27 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3484 mL | 11.7421 mL | 23.4841 mL | |
| 5 mM | 0.4697 mL | 2.3484 mL | 4.6968 mL | |
| 10 mM | 0.2348 mL | 1.1742 mL | 2.3484 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/NCT03462017
Conditions:Microvascular Coronary Artery DiseaseProducts are for research use only; We do not sell to patients
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