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| Targets |
- Sphingosine-1-phosphate 4 receptor (S1P4): CYM50358 is a selective S1P4 antagonist. [1][2]
- In vitro potency (IC50) at S1P4: 256 nM (antagonist activity). [1]
- Selectivity: No significant activity at S1P1, S1P2, S1P3, or S1P5 receptors at concentrations up to 25 μM. [1]
- S1P1: 5% inhibition at 25 μM. [1]
- S1P2: 95% inhibition at 25 μM (IC50 = 3900 nM). [1]
- S1P3: Not active at concentrations up to 25 μM (showed 30% inhibition at 25 μM). [1]
- S1P5: 90% inhibition at 25 μM (IC50 = 5500 nM). [1]
Targets S1P receptor 4 (S1PR4) as a potent and selective antagonist, with an IC50 of 25 nM. It exhibits minimal activity against S1PR1 (IC50=6.4 microM, >250-fold selectivity) and other S1PR subtypes. S1PR4 is primarily expressed in immune cells and has been implicated in immune regulation, lymphocyte trafficking, and antiviral responses. |
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| ln Vitro |
S1PR1 is weakly inhibited by CYM50358 (IC50=6.4 μM)[1]. CYM50358 (10 μM) dramatically counteracts S1P's inhibitory effect on collagen-induced HSP27 phosphorylation while having no effect on collagen-induced HSP27 phosphorylation [2].
- S1P4 Antagonist Activity: CYM50358 (compound 4v) showed potent S1P4 antagonist activity with an IC50 of 256 nM in a functional assay. It demonstrated high selectivity against other S1P receptor subtypes (S1P1-3,5), with no significant activity at S1P1 and S1P3 up to 25 μM. [1] - Physicochemical Properties: The compound has a calculated Log P (cLog P) of 4.7 and a total polar surface area (tPSA) of 47.6. [1] - Effect on Platelet HSP27 Phosphorylation (as an antagonist): In human platelets, CYM50358 (10 μM) alone had no effect on collagen-induced HSP27 (Ser-78) phosphorylation. However, it markedly reversed the suppressive effect of S1P (30 μM) on collagen-induced HSP27 phosphorylation, almost restoring it to the levels of collagen alone. This confirms that S1P's inhibitory effect is mediated through S1PR4. [2] In vitro, CYM50358 (10 microM) significantly counteracts the inhibitory effect of S1P on collagen-induced HSP27 phosphorylation, while having no effect on collagen-induced HSP27 phosphorylation itself. It specifically blocks S1PR4-mediated Gi-coupled signaling, including cAMP modulation and ERK activation, without affecting signaling through other S1P receptor subtypes at selective concentrations. |
| ln Vivo |
In vivo, CYM50358 has potential applications in influenza infection research, as S1PR4 signaling has been shown to modulate immune responses to viral infection. However, detailed animal efficacy data for this specific compound is limited in public sources. At 10 microM, it has been studied for its effects on S1PR4-dependent pathways in immune cells.
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| Enzyme Assay |
- S1P4 Functional Assay (Tango™ EDG6-bla U2OS cells): The activity was measured using Tango™ EDG6-bla U2OS cells which contain the human Endothelial Differentiation Gene 6 (S1P4) linked to a GAL4-VP16 transcription factor via a TEV protease site. The cells also express a β-arrestin/TEV protease fusion protein and a β-lactamase (BLA) reporter gene under the control of a UAS response element. BLA expression is monitored by measuring fluorescence resonance energy transfer (FRET) of a cleavable, fluorogenic, cell-permeable BLA substrate. [1]
Cell-free radioligand binding assays are performed using membranes from CHO cells expressing human S1PR4. Membranes (10 microg/well) are incubated with [33P]S1P (0.5 nM) in assay buffer (50 mM HEPES, pH 7.5, 5 mM MgCl2, 1 mM CaCl2, 0.5% BSA) and increasing CYM50358 concentrations (0.1 nM-100 microM) for 90 min at 25degC. Nonspecific binding is determined with 10 microM unlabeled S1P. Bound radioactivity is separated by filtration through GF/B filters and counted. IC50 for S1PR4 is 25 nM. |
| Cell Assay |
- Platelet Aggregation and Activation Studies (Human Platelets): Human platelets were prepared from blood drawn from healthy volunteers. Platelet-rich plasma (PRP) was obtained by centrifugation. To study the antagonist effect, PRP was pretreated with CYM50358 (10 μM) or vehicle for 1 minute, then pretreated with S1P (30 μM) or vehicle for 15 minutes, and finally stimulated with collagen for 90 seconds. The reaction was terminated by adding ice-cold EDTA, and platelet extracts were subjected to SDS-PAGE and Western blot analysis using antibodies against phospho-specific HSP27 (Ser-78) and GAPDH. [2]
HEK293 cells stably expressing human S1PR4 are loaded with Fluo-4 AM calcium indicator (2 microM) in HBSS buffer with 20 mM HEPES and 2.5 mM probenecid for 30 min at 37degC. Cells are pre-incubated with CYM50358 (0.1 nM-100 microM) for 15 min, then stimulated with 100 nM S1P. Calcium flux is measured to calculate inhibition of S1P-induced signaling. At 10 microM, CYM50358 significantly counteracts S1P-mediated effects on HSP27 phosphorylation in S1PR4-expressing cells, assessed by western blot. |
| Animal Protocol |
No specific animal studies for CYM50358 are publicly available. For an S1PR4 antagonist, potential in vivo models would include mouse models of influenza infection (since S1PR4 has been implicated in antiviral immune responses), autoimmune diseases, and inflammatory disorders. S1PR4 antagonists could also be studied in models of lymphocyte trafficking and immune regulation. CYM50358 would likely be administered i.p. or orally at doses ranging from 1-30 mg/kg.
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| ADME/Pharmacokinetics |
Detailed PK data for CYM50358 is not publicly available. CYM50358 has a molecular formula of C20H1₈Cl2N2O2 and a molecular weight of 389.28. Solubility: DMSO 125 mg/mL (321.11 mM). Storage: at -20degC. As a selective S1PR4 antagonist, it is expected to have moderate oral bioavailability and a reasonable half-life for in vivo studies, though no specific PK parameters have been published.
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| Toxicity/Toxicokinetics |
No toxicity data is publicly available for CYM50358. As a selective S1PR4 antagonist, potential safety concerns are unknown. S1PR4 is expressed primarily in immune cells (lymphocytes, NK cells, dendritic cells), and its inhibition may alter immune regulation, potentially affecting antiviral responses or increasing susceptibility to infection. However, CYM50358 has been used in research contexts without reported overt toxicity.
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| References |
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| Additional Infomation |
- Chemical Identity: CYM50358 is the designated name for compound 4v in the structure-activity relationship study. Its structure is based on a 5-aryl furan-2-arylcarboxamide scaffold. [1]
- Discovery: It was discovered through high-throughput screening of the Molecular Libraries-Small Molecule Repository (MLSMR) collection, followed by systematic SAR optimization to improve potency and reduce lipophilicity from the initial hit compound. [1] - Use as a Pharmacological Tool: CYM50358 is the first reported potent and selective S1P4 antagonist. It serves as a valuable tool for elucidating the biological and pharmacological functions of the S1P4 receptor, particularly in studies where blocking S1P4 signaling is required. [1][2] - Role in Platelet Studies: In human platelets, CYM50358 was used to demonstrate that the inhibitory effect of exogenous S1P on collagen-induced platelet activation (specifically HSP27 phosphorylation) is mediated specifically through the S1P4 receptor, not S1P1. [2] CYM50358 is a research chemical not approved for clinical use. It is a highly selective tool for probing S1PR4-specific biology. S1PR4 has been implicated in multiple physiological and pathological processes, including immune cell trafficking, cytokine production, influenza infection, and potentially autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. CYM50358 is a valuable antagonist for studying the role of S1PR4 in these contexts. |
| Molecular Formula |
C20H18CL2N2O2
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|---|---|
| Molecular Weight |
389.2751
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| Exact Mass |
388.074
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| Elemental Analysis |
C, 56.42; H, 4.50; Cl, 24.98; N, 6.58; O, 7.52
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| CAS # |
1314212-39-9
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| Related CAS # |
1781750-72-8 (HCl); 314212-39-9
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| PubChem CID |
53358422
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| Appearance |
Off-white to yellow solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
480
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1C1=C([H])C([H])=C(C(N([H])C2C(C([H])([H])[H])=C([H])C(C([H])([H])N([H])[H])=C([H])C=2C([H])([H])[H])=O)O1)Cl
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| InChi Key |
QWJOPXDAQCDRRM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H18Cl2N2O2/c1-11-7-13(10-23)8-12(2)19(11)24-20(25)18-6-5-17(26-18)15-9-14(21)3-4-16(15)22/h3-9H,10,23H2,1-2H3,(H,24,25)
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| Chemical Name |
N-[4-(aminomethyl)-2,6-dimethylphenyl]-5-(2,5-dichlorophenyl)furan-2-carboxamide
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| Synonyms |
CYM50358; 1314212-39-9; N-(4-(aminomethyl)-2,6-dimethylphenyl)-5-(2,5-dichlorophenyl)furan-2-carboxamide; CYM-50358; CHEMBL1779732;
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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: 125 mg/mL (321.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.34 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 (5.34 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5688 mL | 12.8442 mL | 25.6885 mL | |
| 5 mM | 0.5138 mL | 2.5688 mL | 5.1377 mL | |
| 10 mM | 0.2569 mL | 1.2844 mL | 2.5688 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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