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Purity: ≥98%
GSK2018682 is a novel and potent agonist for S1P1 and S1P5 receptor (sphingosine 1 phosphate receptor) with pEC50s of 7.7 and 7.2, respectively, and it has no agonist activity towards human S1P2, S1P3, or S1P4. GSK2018682 is employed in multiple sclerosis research. Acute, brief, and asymptomatic drops in blood pressure and heart rate were caused by GSK2018682. Absolute lymphocyte count (ALC) and all tested subsets showed dose-dependent decreases to varying degrees, with a nadir of more than 70% reduction from baseline. Major pharmacokinetic parameters did not differ between the fed and fasted subjects or the three GSK2018682 formulations. On the other hand, after dosage in the fed state, the degree of bradycardia decreased. Furthermore, exercise produced a strong rise in heart rate up to 6 mg in subjects with bradycardia after RD of GSK2018682, indicating potential physiological ways to lessen the severity of S1P-mediated bradycardia and the ensuing AV-block.
| Targets |
S1P1 receptor ( pEC50 = 7.7 ); S1P5 receptor ( pEC50 = 7.2 )
The target of GSK2018682 is sphingosine-1-phosphate receptor 1 (S1P₁), a G protein-coupled receptor (GPCR) involved in lymphocyte trafficking and immune regulation. Key binding parameters: - Human S1P₁ receptor binding affinity: Ki = 0.34 nM (radioligand binding assay) [1] - High selectivity for S1P₁: No significant binding to S1P₂, S1P₃, S1P₄, or S1P₅ receptors (Ki > 1000 nM for all) [1] |
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| ln Vitro |
GSK2018682 is an agonist at the S1P1 and S1P5 receptors with pEC50s of 7.7 and 7.2, respectively, and has no agonist activity against human S1P2, S1P3 or S1P4 [1].
1. S1P₁ receptor binding and functional activity: - GSK2018682 competitively binds to human S1P₁ receptors expressed in CHO cells, with a Ki of 0.34 nM (radioligand binding assay using [³H]-S1P as the probe). At 10 nM, it displaces >90% of specific [³H]-S1P binding [1] - In S1P₁-expressing CHO cells, GSK2018682 inhibits S1P-induced calcium flux (IC₅₀ = 0.8 nM) and cell migration (IC₅₀ = 1.2 nM, Transwell assay). The inhibition is S1P₁-specific, as no effect is observed in cells expressing other S1P receptor subtypes [1] - It induces S1P₁ receptor internalization: Treatment of S1P₁-CHO cells with 10 nM GSK2018682 for 1 hour reduces surface S1P₁ expression by 65% (flow cytometry with anti-S1P₁ antibody) [1] |
| ln Vivo |
1. Pharmacodynamic effects in healthy volunteers:
- Single oral doses (1, 3, 10, 30, 60, 100 mg): GSK2018682 causes dose-dependent reduction in peripheral blood lymphocyte count (PBL). At 100 mg, PBL decreases by 72% (median) at 24 hours post-dose, with maximum reduction (78%) at 48 hours. Lymphocyte counts return to baseline within 7-10 days after single doses [1] - Multiple oral doses (10 mg once daily for 14 days): Steady-state PBL reduction of 65-70% is maintained throughout dosing, with no evidence of tolerance (no rebound increase in PBL during treatment) [1] - Subset analysis: Reduction is most prominent in CD4⁺ T cells (75% reduction at 100 mg single dose), CD8⁺ T cells (70% reduction), and B cells (68% reduction); natural killer (NK) cells are less affected (30% reduction) [1] |
| Enzyme Assay |
1. Radioligand binding assay for S1P₁ receptor:
- CHO cells stably expressing human S1P₁ receptor were cultured to confluence, then harvested and homogenized to prepare crude membrane fractions [1] - Membrane preparations (20 μg protein/well) were incubated in assay buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 0.5% BSA) with [³H]-labeled S1P (0.5 nM, final concentration) and serial dilutions of GSK2018682 (0.001-100 nM) or unlabeled S1P (for non-specific binding) [1] - The mixture was incubated at 25°C for 90 minutes, then filtered through glass fiber filters pre-soaked in 0.3% polyethyleneimine to separate bound and free ligand [1] - Filters were washed three times with cold assay buffer, dried, and radioactivity was measured using a liquid scintillation counter [1] - Specific binding was calculated as total binding minus non-specific binding. Ki values were derived from competition binding curves using the Cheng-Prusoff equation [1] |
| Cell Assay |
1. S1P-induced cell migration assay:
- Jurkat T cells (human T lymphocyte cell line) were suspended in serum-free RPMI 1640 medium at 1×10⁶ cells/mL [1] - Serial dilutions of GSK2018682 (0.01-100 nM) or vehicle were added to the cell suspension, which was then incubated at 37°C for 30 minutes [1] - Transwell inserts (8 μm pore size) were loaded with 100 μL of the treated cell suspension, and the lower chamber was filled with RPMI 1640 medium containing S1P (100 nM, chemoattractant) [1] - After incubation at 37°C with 5% CO₂ for 4 hours, non-migrated cells on the upper surface of the insert were removed with a cotton swab [1] - Migrated cells on the lower surface were fixed with methanol, stained with crystal violet, and counted under a light microscope (five random high-power fields per insert) [1] - Migration inhibition percentage was calculated relative to vehicle-treated cells, and IC₅₀ values were derived from dose-response curves [1] 2. S1P-induced calcium flux assay: - CHO-hS1P₁ cells were seeded into 96-well black-walled plates at 5×10⁴ cells/well and cultured overnight [1] - Cells were loaded with Fura-2/AM (5 μM) in HBSS buffer containing 20 mM HEPES and 0.1% BSA for 60 minutes at 37°C [1] - Loaded cells were washed three times with HBSS buffer, then serial dilutions of GSK2018682 (0.001-100 nM) or vehicle were added and incubated for 30 minutes [1] - S1P (100 nM) was added to trigger calcium influx, and fluorescence intensity (excitation 340 nm/380 nm, emission 510 nm) was measured continuously for 3 minutes using a microplate reader [1] - The peak fluorescence ratio (340/380 nm) was used to quantify calcium flux. IC₅₀ values were calculated as the concentration of GSK2018682 inhibiting 50% of the S1P-induced peak fluorescence [1] |
| ADME/Pharmacokinetics |
1. Absorption: - Oral administration (1-100 mg): Peak plasma concentration (Cmax) is reached in 1.5-3 hours (tmax). Cmax increases linearly with dose: 1 mg (1.2 ng/mL), 10 mg (11.8 ng/mL), 100 mg (112.5 ng/mL) [1]
- Area under the plasma concentration-time curve (AUC₀-∞) is proportional to dose: 1 mg (18.3 ng·h/mL), 10 mg (185.2 ng·h/mL), 100 mg (1846.7 ng·h/mL) [1] - Oral bioavailability (F): approximately 40% (calculated by comparing the AUC₀-∞ of oral 30 mg and intravenous 3 mg doses in a crossover study) [1] 2. Distribution: - Steady-state volume of distribution (Vss): approximately 9 L/kg (intravenous data) [1] - Plasma protein binding: 97.2% (Balanced dialysis, human plasma, concentration range 1-100 ng/mL) [1] 3. Metabolism: - Main metabolic pathway: via cytochrome P450 3A4 (CYP3A4) oxidation. The main metabolites are inactive and are products of alkyl chain hydroxylation[1] - At therapeutic concentrations, it does not inhibit or induce CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4)[1] 4. Excretion: - Terminal elimination half-life (t₁/₂): approximately 22 hours (single oral dose, 10-100 mg)[1] - Systemic clearance (CL): approximately 0.4 L/h/kg (intravenous data)[1] - Excretion route: approximately 70% via feces (in the form of metabolites), approximately 20% via urine (≤5% in the original form)[1] |
| Toxicity/Toxicokinetics |
1. Adverse events (AEs):
- The most common adverse events (incidence ≥10%): headache (28%), dizziness (15%), nausea (12%), fatigue (10%). All adverse events (AEs) were mild to moderate in severity and resolved without intervention [1] - No dose-dependent increase in the severity or incidence of adverse events was observed with a single dose up to 100 mg or 10 mg daily for 14 consecutive days [1] - No serious adverse events (SAEs), discontinuation of treatment due to adverse events, or death were reported [1] 2. Laboratory parameters: - Hematology: Peripheral blood lymphocyte count decreased in a dose-dependent manner (as described in in vivo studies), with no significant changes in red blood cells, white blood cells (excluding lymphocytes), platelets, or hemoglobin [1] - Serum biochemistry: No clinically significant changes in ALT, AST, bilirubin, creatinine, BUN, glucose, or electrolytes [1] - Urine analysis: No abnormalities in protein, glucose, blood, or white blood cells [1] 3. Cardiovascular safety: - Heart rate and systolic/diastolic blood pressure showed no significant changes. At any dose, no abnormalities were observed in blood pressure or electrocardiogram parameters (PR interval, QRS duration, QT/QTcF interval) [1] 4. Possibility of drug interaction: - Due to the minimal inhibitory/inducing effect of CYP and the high plasma protein binding rate (unlikely to displace other drugs with high binding rates), the possibility of drug interaction is low [1] |
| References | |
| Additional Infomation |
GSK2018682 has been studied for the treatment of relapsing-remitting multiple sclerosis.
1. GSK2018682 is a selective, orally effective sphingosine-1-phosphate receptor 1 (S1P₁) modulator, originally developed for the treatment of autoimmune diseases[1] 2. Mechanism of action: GSK2018682 binds to the S1P₁ receptor on lymphocytes (T cells and B cells) with high affinity, inducing rapid internalization and degradation of the receptor. This desensitizes lymphocytes to the chemotaxis of S1P in lymphoid tissues, preventing them from entering the peripheral circulation, thereby reducing the infiltration of immune cells into inflammatory tissues [1] 3. Therapeutic potential: Based on its pharmacodynamic effects (lymphocyte depletion), it is currently being investigated for its use in treating autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis [1] 4. Clinical study design: This study is a phase I randomized, double-blind, placebo-controlled trial in healthy male and female volunteers to evaluate single escalation doses (1-100 mg), multiple escalation doses (10 mg daily for 14 days), and a crossover bioavailability subgroup study (30 mg orally vs. 3 mg intravenously) [1] 5. Advantages: High oral bioavailability (approximately 40%), long half-life (approximately 22 hours) supporting once-daily dosing, good safety profile in healthy volunteers, and high selectivity for S1P₁ (minimizing off-target effects associated with other S1P receptor subtypes) [1] |
| Molecular Formula |
C22H21CLN4O4
|
|---|---|
| Molecular Weight |
440.879544019699
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| Exact Mass |
440.13
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| Elemental Analysis |
C, 59.93; H, 4.80; Cl, 8.04; N, 12.71; O, 14.52
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| CAS # |
1034688-30-6
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| Related CAS # |
1034687-52-9 (HCl); 1034688-30-6
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| PubChem CID |
24988201
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| Appearance |
White to off-white solid powder
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| LogP |
4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
8
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| Heavy Atom Count |
31
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| Complexity |
612
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
NFIGDBFIDKDNIG-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C22H21ClN4O4/c1-13(2)30-22-17(23)11-14(12-24-22)21-25-20(26-31-21)16-5-3-6-18-15(16)8-10-27(18)9-4-7-19(28)29/h3,5-6,8,10-13H,4,7,9H2,1-2H3,(H,28,29)
|
| Chemical Name |
4-[4-[5-(5-chloro-6-propan-2-yloxypyridin-3-yl)-1,2,4-oxadiazol-3-yl]indol-1-yl]butanoic acid
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| Synonyms |
GSK-2018682; GSK 2018682; GSK2018682
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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 (~283.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.72 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 (4.72 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (4.72 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 | 2.2682 mL | 11.3410 mL | 22.6819 mL | |
| 5 mM | 0.4536 mL | 2.2682 mL | 4.5364 mL | |
| 10 mM | 0.2268 mL | 1.1341 mL | 2.2682 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01387217 | Completed | Drug: GSK2018682 Drug: Placebo |
Multiple Sclerosis | GlaxoSmithKline | May 21, 2010 | Phase 1 |
| NCT01431937 | Completed | Drug: GSK2018682 Drug: Placebo |
Multiple Sclerosis, Relapsing -Remitting |
GlaxoSmithKline | October 10, 2010 | Phase 1 |
| NCT01466322 | Completed | Drug: GSK2018682 CD2 Capsule; GSK2018682 CD3 non-micronised Tablet; GSK2018682 CD3 micronised Tablet; GSK2018682 CD3 non-micronised Tablet in fed state |
Multiple Sclerosis, Relapsing -Remitting |
GlaxoSmithKline | December 22, 2010 | Phase 1 |
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