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GSK805 (GSK-805) is a novel, potent, and orally bioavailable RORγt inhibitor with the potential to be used for autoimmune encephalomyelitis (EAE). It inhibits RORγγ with pIC50 of 8.4 and >8.2 for RORγ FRET assay and Th17 assay. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. GSK805 demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.
| ln Vitro |
Th17 cell responses are inhibited by GSK805 (0.5 μM; 4 d) [2]. Assay for cell differentiation [2]
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| ln Vivo |
Mice with experimental autoimmune encephalomyelitis (EAE) respond better to GSK805 (10 mg/kg) administered orally once daily for 35 days [2]. In EAE mice, GSK805 (30 mg/kg; once oral) can suppress the Th17 cell response [2].
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| Cell Assay |
Cell differentiation assay[2]
Cell Types: CD4+ T cells Tested Concentrations: 0.5 μM Incubation Duration: 4 days Experimental Results: Inhibition of IL-17 production during Th17 cell differentiation. |
| Animal Protocol |
Animal/Disease Models: Use MOG35-55 plus CFA to immunize C57BL/6 mice [2]
Doses: 10 mg/kg Route of Administration: po (oral gavage); 10 mg/kg, one time/day; Last for 35 days Experimental Results: Effectively improved EAE in mice severity. Animal/Disease Models: C57BL/6 mice with EAE [2] Doses: 30 mg/kg Route of Administration: po (oral gavage); 30 mg/kg Primary Experimental Results: IFN-γ-IL-17+ and IFN in EAE mice -γ+IL-17+ T cells diminished but did not change the frequency of TNF-α+ T cells. |
| References |
[1]. Wang Y, et al. Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors. ACS Med Chem Lett. 2015 May 26;6(7):787-792.
[2]. Xiao S, et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity. 2014 Apr 17;40(4):477-89. |
| Molecular Formula |
C23H18CL2F3NO4S
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|---|---|
| Molecular Weight |
532.3595
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| CAS # |
1426802-50-7
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| SMILES |
O=C(NC1=CC(Cl)=C(C2=CC=CC=C2OC(F)(F)F)C(Cl)=C1)CC3=CC=C(S(=O)(CC)=O)C=C3
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| InChi Key |
CEICQMBWAQAIQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H18Cl2F3NO4S/c1-2-34(31,32)16-9-7-14(8-10-16)11-21(30)29-15-12-18(24)22(19(25)13-15)17-5-3-4-6-20(17)33-23(26,27)28/h3-10,12-13H,2,11H2,1H3,(H,29,30)
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| Chemical Name |
N-[2,6-dichloro-2'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]-4-(ethylsulfonyl)-benzeneacetamide
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| Synonyms |
RORγt Inverse Agonist II; GSK-805; GSK 805; GSK805; ROR gamma-t-IN-1;
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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 : ≥ 100 mg/mL (~187.84 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.70 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 (4.70 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 | 1.8784 mL | 9.3921 mL | 18.7843 mL | |
| 5 mM | 0.3757 mL | 1.8784 mL | 3.7569 mL | |
| 10 mM | 0.1878 mL | 0.9392 mL | 1.8784 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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