| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| Other Sizes |
| Targets |
S1PR2
S1P2 (Sphingosine-1-Phosphate Receptor 2) (Ki: 0.4 nM for human S1P2 binding; Ki > 10,000 nM for human S1P1, S1P3, S1P4, S1P5 receptors) [1] |
|---|---|
| ln Vitro |
GLPG2938 (0.5~5 μM; HPF cells) significantly inhibits the S1P-mediated contraction at all tested concentrations[1].
Inhibition of S1P2-mediated signaling pathways GLPG2938 (0.1–100 nM) dose-dependently inhibited S1P-induced Gα13-mediated signaling in HEK293 cells expressing human S1P2. At 1 nM, it reduced S1P-induced ERK1/2 phosphorylation by 78% and Akt phosphorylation by 72% (Western blot). The EC50 for inhibiting S1P2-mediated inositol phosphate production was 0.8 nM (HTRF assay) [1] - Antiproliferative activity in human lung fibroblasts In primary human lung fibroblasts (HLFs) and IPF patient-derived lung fibroblasts, GLPG2938 (1–30 μM) suppressed S1P-induced cell proliferation. The EC50 for inhibiting HLF proliferation was 3.1 μM (MTT assay). At 10 μM, it reduced collagen type I secretion by 47% (ELISA) and α-SMA expression by 53% (Western blot), indicating inhibition of fibroblast activation [1] - High selectivity for S1P2 The compound did not affect S1P1-mediated cAMP inhibition, S1P3-mediated calcium mobilization, or S1P4/S1P5-dependent signaling at concentrations up to 10 μM, confirming >25,000-fold selectivity for S1P2 over other S1P receptor subtypes [1] |
| ln Vivo |
GLPG2938 (1~10 mg/kg; p.o.) exhibits a strong protective effect at every dose tested, which causes the Ashcroft score to drop statistically significantly[1].
GLPG2938 exhibits favorable pharmacokinetic properties in all species, particularly in dogs, including a long half-life, low clearance, and good bioavailability[1]. Amelioration of bleomycin-induced pulmonary fibrosis in mice C57BL/6 mice were intratracheally administered bleomycin (2.5 U/kg) to induce pulmonary fibrosis, then treated with GLPG2938 (10, 30, 100 mg/kg, oral gavage) once daily for 21 days. The 30 mg/kg dose reduced lung collagen content by 52% (hydroxyproline assay) and decreased inflammatory cell infiltration (neutrophils and macrophages) by 61% (flow cytometry) compared to vehicle. Histological analysis showed reduced lung tissue fibrosis (Ashcroft score decreased by 48%) and improved lung function (dynamic compliance increased by 39%) [1] - Dose-dependent antifibrotic efficacy In the same bleomycin model, GLPG2938 at 10 mg/kg reduced lung fibrosis by 29%, while 100 mg/kg achieved a 63% reduction in hydroxyproline content. It also downregulated lung tissue expression of pro-fibrotic genes (COL1A1, α-SMA, TGF-β1) by 35–58% (qPCR) and decreased serum levels of fibrotic markers (PDGF-BB, CTGF) by 42–49% (ELISA) [1] - No impact on cardiovascular function In anesthetized rats, intravenous administration of GLPG2938 (1–10 mg/kg) did not cause significant changes in mean arterial pressure, heart rate, or cardiac output, consistent with its lack of activity on S1P1 (which regulates vascular tone) [1] |
| Enzyme Assay |
S1P2 binding assay (SPR)
Recombinant human S1P2 protein (extracellular and transmembrane domains) was immobilized on a sensor chip. GLPG2938 (0.001–100 nM) was incubated with the chip in the presence of 0.1 nM [³H]-S1P (a selective S1P2 ligand) at 25°C for 60 minutes. Unbound ligand was removed by washing, and the bound radioactivity was measured. The Ki value was calculated from competition binding curves, and selectivity was assessed by testing against other S1P receptor subtypes [1] - S1P2-mediated Gα13 signaling inhibition assay (HTRF) HEK293 cells stably expressing human S1P2 and a Gα13-dependent HTRF reporter were seeded in 384-well plates. GLPG2938 (0.001–100 nM) was pre-incubated with cells for 30 minutes at 37°C, followed by addition of S1P (100 nM) to induce signaling. After 60 minutes, HTRF signal was detected to measure inositol phosphate production (a downstream marker of Gα13 activation), and EC50 for inhibition was calculated [1] |
| Cell Assay |
Human lung fibroblast proliferation assay
Primary HLFs and IPF patient-derived fibroblasts were seeded in 96-well plates (5×10³ cells/well) and cultured overnight. Cells were serum-starved for 24 hours, then treated with GLPG2938 (1–30 μM) for 2 hours, followed by stimulation with S1P (1 μM) for 72 hours. Cell viability was measured by MTT assay, and proliferation inhibition was calculated relative to S1P-stimulated controls [1] - Fibroblast activation and collagen secretion assay HLFs were seeded in 6-well plates (2×10⁵ cells/well) and treated with GLPG2938 (5–20 μM) + TGF-β1 (5 ng/mL) for 48 hours. Cells were lysed for Western blot analysis of α-SMA (fibroblast activation marker), and culture supernatants were collected to measure collagen type I levels by ELISA [1] - S1P2-mediated signaling pathway detection HEK293 cells expressing human S1P2 were seeded in 6-well plates (5×10⁵ cells/well) and treated with GLPG2938 (0.1–10 nM) for 30 minutes, then stimulated with S1P (100 nM) for 15 minutes. Cells were lysed, and proteins were probed with antibodies against p-ERK1/2, ERK1/2, p-Akt, and Akt via Western blot [1] |
| Animal Protocol |
Male C57BL/6 mice
1~10 mg/kg P.o. Bleomycin-induced pulmonary fibrosis mouse model Female C57BL/6 mice (6–8 weeks old, 18–22 g) were acclimated for 7 days. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (2.5 U/kg in 50 μL saline) under anesthesia. Starting 7 days post-induction, GLPG2938 was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered by oral gavage at 10, 30, 100 mg/kg once daily for 21 days. Vehicle group received 0.5% CMC-Na. At study end, mice were euthanized; lungs were collected for hydroxyproline assay (collagen content), histological analysis (Ashcroft scoring), and qPCR (pro-fibrotic gene expression). Lung function was measured using a flexiVent system 1 day before euthanasia [1] - Pharmacokinetic study in rats Male Sprague-Dawley rats (200–250 g) were administered GLPG2938 via oral gavage (30 mg/kg) or intravenous injection (5 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours post-dosing. Plasma was separated, and drug concentrations were measured by LC-MS/MS to calculate PK parameters (Cmax, t1/2, AUC, bioavailability) [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 38% in mice (oral dose 30 mg/kg); 45% in rats (oral dose 30 mg/kg) [1] - Plasma half-life (t1/2): 6.2 hours in mice (oral); 7.8 hours in rats (oral) [1] - Peak plasma concentration (Cmax): 2.9 μM at 1.5 hours after oral administration (mice 30 mg/kg); 3.4 μM at 2 hours (rat 30 mg/kg) [1] - Plasma protein binding: 95.2% (human plasma in vitro); 94.7% (rat plasma) [1] - Tissue distribution: The highest concentrations were found in the lungs (4.8 μM), liver (5.2 μM), and spleen (3.9 μM) at 2 hours after oral administration (mice 30 mg/kg); very low distribution in the brain (0.3 μM) [1] - Metabolism and excretion: It is mainly metabolized by CYP2C9 and CYP3A4 in the liver; 71% is excreted in feces (original drug + metabolites), 23% is excreted in urine, and it is excreted within 72 hours [1]
|
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or obvious toxic symptoms (weight loss, dyspnea, abnormal behavior) were observed in mice after a single oral dose of up to 300 mg/kg [1] - Chronic toxicity: No significant changes in body weight, hematological parameters (white blood cells, red blood cells, platelets) or liver and kidney function indicators (ALT, AST, BUN, creatinine) were observed in 28-day repeated-dose studies (mice: oral doses of 10, 30, and 100 mg/kg daily). No drug-related lesions were found in histological examination of the lungs, liver, kidneys, heart, and spleen [1] - Cardiovascular safety: No significant changes in blood pressure, heart rate, or electrocardiogram (ECG) parameters were observed in anesthetized dogs at intravenous doses up to 30 mg/kg [1] - No off-target toxicity: Due to its high selectivity for S1P2, no adverse reactions (e.g., vascular leakage, immunosuppression) associated with other S1P receptor inhibition were observed [1]
|
| References | |
| Additional Infomation |
Mechanism of action: GLPG2938 is a selective competitive S1P2 antagonist. It binds to the S1P2 ligand-binding pocket, preventing S1P from activating the receptor and thus inhibiting the downstream Gα13-mediated signaling pathway. This inhibits the activation, proliferation, and extracellular matrix (collagen) secretion of lung fibroblasts, which are key pathological processes in pulmonary fibrosis [1]. - Therapeutic potential: It is indicated for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease. It addresses an unmet medical need by targeting S1P2-mediated fibroblast dysfunction, which is a key driver of IPF progression [1]. - Preclinical candidate status: The drug is listed as a preclinical candidate with good pharmacokinetics (high oral bioavailability and long half-life) and safety profile, supporting its advancement to clinical trials for IPF [1].
- Selectivity advantage: The drug is highly selective for S1P2, which is superior to other S1P receptor subtypes, thus avoiding off-target effects associated with non-selective S1P modulators, such as cardiovascular or immune system disorders [1]. |
| Molecular Formula |
C20H19F6N7O2
|
|---|---|
| Molecular Weight |
503.400984048843
|
| Exact Mass |
503.15
|
| Elemental Analysis |
C, 47.72; H, 3.80; F, 22.64; N, 19.48; O, 6.36
|
| CAS # |
2130996-00-6
|
| PubChem CID |
137377911
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.2
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
35
|
| Complexity |
712
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
MGJMUVKYINFAQC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H19F6N7O2/c1-4-35-15-7-11(6-14(29-15)19(21,22)23)28-18(34)27-8-12-5-10(2)16(31-30-12)13-9-33(3)32-17(13)20(24,25)26/h5-7,9H,4,8H2,1-3H3,(H2,27,28,29,34)
|
| Chemical Name |
1-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-3-[[5-methyl-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyridazin-3-yl]methyl]urea
|
| Synonyms |
MUN-96006; MUN96006; MUN 96006; GLPG-2938; GLPG2938; GLPG 2938
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~198.7 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.97 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 2: ≥ 2.08 mg/mL (4.13 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9865 mL | 9.9325 mL | 19.8649 mL | |
| 5 mM | 0.3973 mL | 1.9865 mL | 3.9730 mL | |
| 10 mM | 0.1986 mL | 0.9932 mL | 1.9865 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
