GSK2245035 (GSK-2245035) is a novel potent and selective intranasal Toll-like receptor 7 (TLR7) agonist with Type-1 interferon (IFN)-stimulating activity and the potential to be used for the treatment of asthma. Exhibits pEC50s of 9.3 and 6.5 for IFNα and TFNα. Suppresses allergen-induced Th2 cytokine production in human peripheral blood cell cultures.
Physicochemical Properties
| Molecular Formula | C20H34N6O2 |
| Molecular Weight | 390.522964000702 |
| Exact Mass | 390.274 |
| CAS # | 1207629-49-9 |
| Related CAS # | 1207629-49-9;1325212-97-2; |
| PubChem CID | 44623937 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.1±0.1 g/cm3 |
| Index of Refraction | 1.555 |
| LogP | 3.37 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 28 |
| Complexity | 487 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CCC[C@H](C)OC1=NC(=C2C(=N1)N(C(=O)N2)CCCCCN3CCCCC3)N |
| InChi Key | LFMPVTVPXHNXOT-HNNXBMFYSA-N |
| 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 |
| Chemical Name | 6-amino-2-[(2S)-pentan-2-yl]oxy-9-(5-piperidin-1-ylpentyl)-7H-purin-8-one |
| 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) |
Biological Activity
| 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]. |
| 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]. |
| 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. |
| References |
[1]. Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma. J Med Chem. 2016 Mar 10;59(5):1711-26. |
| Additional Infomation | GSK2245035 is under investigation in clinical trial NCT02833974 (Effect of the GSK2245035 on the Allergen-induced Asthmatic Response). |
Solubility Data
| Solubility (In Vitro) | DMSO : ~125 mg/mL (~320.09 mM) |
| 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. 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. 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 | 2.5607 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 |