| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Targets |
Toll-like receptor 7 (TLR7). GSK2245035 is a highly selective intranasal TLR7 agonist.
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| ln Vitro |
In individual-derived human PBMC cells, GSK2245035 (0.01, 0.1, 1, 10, 100, 1000, and 10,000 nM; 6 days) decreases the release of Th2 cytokines, IL-5 and IL-13, in response to home dust mites or Timothy. Dose-dependent sensitization levels to certain allergens exist [1].
GSK2245035 is a highly potent and selective TLR7 agonist with pEC50 values of 9.3 for IFNα and 6.5 for TNFα. It suppresses Th2 cytokine responses to allergens in human cell cultures. The compound causes local upregulation of TLR7-mediated cytokines (IP-10) in vivo after intranasal administration at very low doses. GSK2245035 preferentially induces the production of interferon alpha (IFNα) versus tumor necrosis factor alpha (TNFα). |
| ln Vivo |
At dosages of 0.3 mg/kg and higher, GSK2245035 (in; 0.03-1 mg/kg; 6 hours) causes a dose-related rise in serum IFNα levels at the 2-hour time point that disappears at 6 hours [1]. After administering GSK2245035 (3, 30, 300, and 3000 ng/kg) for six hours, the most sensitive biomarker of target engagement, plasma IP-10, was found to be enhanced in cynomolgus monkeys at the 30 ng/kg dose and higher [1].
In vivo, GSK2245035 causes local upregulation of TLR7-mediated cytokines (IP-10) after intranasal administration at very low doses. It suppresses Th2 cytokine responses to allergens. Target engagement post administration was clearly demonstrated by increases in serum and nasal IP-10, with a consistently high posterior probability of increases in mean IP-10 confirming target engagement. Single and repeat GSK2245035 intranasal administration has an acceptable safety profile at doses that induce local TLR7-mediated immune responses. In a Phase II clinical trial (NCT02833974), although target engagement was observed, GSK2245035 did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. A randomized, double-blind, placebo-controlled study found that intranasal GSK2245035 does not attenuate the allergen-induced asthmatic response. |
| Enzyme Assay |
TLR7 agonist activity is assessed using in vitro cell-based assays measuring Type-1 interferon production. Cells expressing TLR7 (e.g., HEK293-TLR7, plasmacytoid dendritic cells, or PBMCs) are treated with GSK2245035 at various concentrations (typically 0.001-100 μM) and IFNα or other cytokine levels are measured by ELISA or multiplex assays. pEC50 values are calculated from dose-response curves using nonlinear regression analysis. Selectivity is evaluated by testing against other TLR family members (TLR3, TLR8, TLR9).
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| Cell Assay |
Cellular activity is evaluated in human cell cultures including PBMCs, plasmacytoid dendritic cells, or bronchial epithelial cells. Cells are treated with GSK2245035 at various concentrations (typically 0.001-100 μM) for appropriate time periods (4-24 hours for cytokine production). Th2 cytokine responses to allergens (IL-4, IL-5, IL-13) are measured by ELISA or multiplex assays. TLR7-mediated cytokine production (IP-10, IFNα) is assessed by ELISA or qRT-PCR. Type I IFN-stimulated gene expression (ISG15, MX1, IFIT1) is measured by qRT-PCR.
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| Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse[1]
Doses: 0.03, 0.1, 0.3, 1 mg/kg Route of Administration: Intranasally (in); 6 hrs (hours) Experimental Results: Dose-related increases in IFNα levels in serum were detected at doses of 0.3 mg /kg and above at the 2 h time point which had subsided at 6 h. In vivo efficacy is studied in animal models of asthma or allergic airway inflammation. GSK2245035 is administered intranasally at very low doses (typically in the nanogram to microgram range). Airway inflammation is assessed by bronchoalveolar lavage (BAL) fluid cell counts (eosinophils, neutrophils), histological analysis of lung tissue, and measurement of Th2 cytokine levels in BAL fluid and lung homogenates. TLR7-mediated cytokine responses (IP-10, IFNα) are measured in nasal lavage fluid, serum, and lung tissue. In clinical trials, target engagement is confirmed by measuring IP-10 increases in serum and nasal samples. GSK2245035 has been investigated in Phase I and Phase II clinical trials for asthma and allergic rhinitis. |
| ADME/Pharmacokinetics |
GSK2245035 has a molecular formula of C20H22N6O3 and a molecular weight of 394.43 g/mol. CAS Number: 1207629-49-9. It is a selective intranasal TLR7 agonist. Purity: typically ≥98% by HPLC. The compound is soluble in DMSO and should be stored at -20°C for long-term stability, protected from light and moisture. Detailed pharmacokinetic parameters including half-life, bioavailability, and metabolic pathways are available from clinical development studies.
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| Toxicity/Toxicokinetics |
Safety data for GSK2245035 are available from clinical trials. Single and repeat GSK2245035 intranasal administration has an acceptable safety profile at doses that induce local TLR7-mediated immune responses. As a TLR7 agonist, it may cause local inflammatory responses including nasal irritation, rhinorrhea, and cytokine release. The compound is for research use only and has been investigated in clinical development for asthma treatment. Standard laboratory safety practices should be followed, including the use of personal protective equipment and biological safety cabinets. Consult the material safety data sheet (MSDS) for detailed safety information.
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| References | |
| Additional Infomation |
GSK2245035 is being studied in the clinical trial NCT02833974 (the effect of GSK2245035 on allergen-induced asthma response).
GSK2245035 is a research compound and selective intranasal TLR7 agonist with potential for the treatment of asthma. It is not approved for clinical use. The compound has been investigated in multiple clinical trials including Phase I (NCT01480271) and Phase II (NCT01788813, NCT02446613, NCT01607372, NCT03707678, NCT02833974) for asthma and allergic rhinitis. Although target engagement was confirmed by IP-10 increases, GSK2245035 did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. GSK2245035 is a valuable tool for studying TLR7 biology and Type I interferon responses in the context of allergic airway disease. |
| Molecular Formula |
C20H34N6O2
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|---|---|
| Molecular Weight |
390.522964000702
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| Exact Mass |
390.274
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| CAS # |
1207629-49-9
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| Related CAS # |
1207629-49-9;1325212-97-2;
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| PubChem CID |
44623937
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Index of Refraction |
1.555
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| LogP |
3.37
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
28
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| Complexity |
487
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCC[C@H](C)OC1=NC(=C2C(=N1)N(C(=O)N2)CCCCCN3CCCCC3)N
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| InChi Key |
LFMPVTVPXHNXOT-HNNXBMFYSA-N
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| InChi Code |
InChI=1S/C20H34N6O2/c1-3-10-15(2)28-19-23-17(21)16-18(24-19)26(20(27)22-16)14-9-5-8-13-25-11-6-4-7-12-25/h15H,3-14H2,1-2H3,(H,22,27)(H2,21,23,24)/t15-/m0/s1
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| Chemical Name |
6-amino-2-[(2S)-pentan-2-yl]oxy-9-(5-piperidin-1-ylpentyl)-7H-purin-8-one
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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 (~320.09 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.33 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 (5.33 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 (5.33 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 | 2.5607 mL | 12.8034 mL | 25.6069 mL | |
| 5 mM | 0.5121 mL | 2.5607 mL | 5.1214 mL | |
| 10 mM | 0.2561 mL | 1.2803 mL | 2.5607 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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