GSK'481 is a novel, potent and selective inhibitor of RIP1 (receptor interacting protein 1) WT S166 phosphorylation in human vs mouse plasmids overexpressed in HEK293T cells. Receptor Interacting Protein 1 (RIP1) Kinase has emerged as a very promising target for the treatment of numerous inflammatory diseases as a result of the recent discovery of its function in tumor necrosis factor (TNF)-mediated inflammation. This benzoxazepinone template's favorable developability profile, as demonstrated by compound GSK'481, makes it a great place to start for further optimization into a RIP1 clinical candidate.
Physicochemical Properties
| Molecular Formula | C21H19N3O4 |
| Molecular Weight | 377.393265008926 |
| Exact Mass | 377.137 |
| Elemental Analysis | C, 66.83; H, 5.07; N, 11.13; O, 16.96 |
| CAS # | 1622849-58-4 |
| Related CAS # | 1622849-58-4 |
| PubChem CID | 90351311 |
| Appearance | Light brown to brown solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 677.0±55.0 °C at 760 mmHg |
| Flash Point | 363.2±31.5 °C |
| Vapour Pressure | 0.0±2.1 mmHg at 25°C |
| Index of Refraction | 1.653 |
| LogP | 2.06 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 28 |
| Complexity | 566 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | O1C(CC2=CC=CC=C2)=CC(C(N[C@@H]2C(=O)N(C)C3=CC=CC=C3OC2)=O)=N1 |
| InChi Key | KNOUWGGQMADIBV-KRWDZBQOSA-N |
| InChi Code | InChI=1S/C21H19N3O4/c1-24-18-9-5-6-10-19(18)27-13-17(21(24)26)22-20(25)16-12-15(28-23-16)11-14-7-3-2-4-8-14/h2-10,12,17H,11,13H2,1H3,(H,22,25)/t17-/m0/s1 |
| Chemical Name | 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,2-oxazole-3-carboxamide |
| Synonyms | GSK481; GSK 481; GSK-481 |
| 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
| Targets | RIP1 (IC50 = 1.3 nM) |
| ln Vitro | The fact that GSK481 (300 nM; 2 hours; Jurkat cells) reverses the RIP3 up-regulation induced by both TNFa and shikonin in both live and dead cells suggests that necroptosis is in fact induced by both substances[2]. |
| ln Vivo | Three mouse RIP1 mutants exhibit more potent GSK481 inhibition of Ser166 phosphorylation than wild-type mice (IC50 = 18–110 nM)[1]. |
| References |
[1]. DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors. J Med Chem, 2016 Mar 10, 59(5):2163-78. [2]. Simultaneous flow cytometric immunophenotyping of necroptosis, apoptosis and RIP1-dependent apoptosis. Methods. 2018 Feb 1;134-135:56-66. |
Solubility Data
| Solubility (In Vitro) | DMSO: 35~75 mg/mL (92.7~198.7 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.62 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 25.0 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: 2.5 mg/mL (6.62 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 25.0 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: ≥ 2.5 mg/mL (6.62 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6498 mL | 13.2489 mL | 26.4978 mL | |
| 5 mM | 0.5300 mL | 2.6498 mL | 5.2996 mL | |
| 10 mM | 0.2650 mL | 1.3249 mL | 2.6498 mL |