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| 25mg |
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Lanraplenib (also known as GS-9876; GS-SYK) is a highly selective and orally bioavailable Spleen Tyrosine Kinase (SYK) inhibitor with IC50 of 9.5 nM). Gilead is now working on developing it to treat inflammatory conditions like RA. A variety of hematopoietic cells, including B cells, monocytes, macrophages, dendritic cells, and osteoclasts, are involved in the onset and progression of RA. Spleen Tyrosine Kinase (SYK) mediates signaling in these cells. SYK has been shown in animal models of disease and cellular data to be a strong preclinical target for RA therapy. Through the glycoprotein VI (GPVI) receptor, lenraplenib (GS-9876) inhibits SYK activity in platelets without extending the bleeding time (BT) in humans or monkeys. After a once-daily dosage, GS-9876 exhibits outstanding in vivo efficacy in rat CIA models by potently inhibiting several cellular events linked to RA pathogenesis. Comparing GS-9876 to rival SYK programs, selectivity has significantly increased. These findings may lead to an enhanced safety profile for GS-9876 when it comes to inflammatory diseases.
| Targets |
SYK (IC50 = 9.5 nM)
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|---|---|
| ln Vitro |
Lanraplenib succinate (GS-9876 succinate) inhibits the phosphorylation of AKT, BLNK, BTK, ERK, MEK, and PKCδ in human B cells stimulated by anti-IgM with EC50 values ranging from 24-51 nM. he anti-IgM mediated expression of CD69 and CD86 on B-cells (EC50=112±10 nM and 164±15 nM, respectively) as well as the co-stimulated B cell proliferation (EC50=108±55 nM) are inhibited by lanraplenib monosuccinate. Lanraplenib succinate (EC50=121±77 nM and 9±17 nM, respectively) inhibits the release of TNFα and IL-1β when IC is stimulated in human macrophages[1].
Lanraplenib succinate (GS-9876 succinate) prevents platelet activation and aggregation in human whole blood, platelet binding to collagen under arterial flow, and phosphorylation of the linker for T cell activation and phospholipase Cγ2 caused by glycoprotein VI (GPVI)[2]. |
| References |
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| Molecular Formula |
C₂₃H₂₅N₉O.₃/₂C₄H₆O₄
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|---|---|
| Molecular Weight |
620.64
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| Exact Mass |
1240.52
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| Elemental Analysis |
C, 56.12; H, 5.52; N, 20.31; O, 18.04
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| CAS # |
1800047-00-0
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| Related CAS # |
Lanraplenib;1800046-95-0;Lanraplenib monosuccinate;1800046-97-2
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| Appearance |
Solid powder
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| SMILES |
C1CN(CCN1C2COC2)C3=CC=C(C=C3)NC4=NC(=CN5C4=NC=C5)C6=CN=CC(=N6)N.C1CN(CCN1C2COC2)C3=CC=C(C=C3)NC4=NC(=CN5C4=NC=C5)C6=CN=CC(=N6)N.C(CC(=O)O)C(=O)O.C(CC(=O)O)C(=O)O.C(CC(=O)O)C(=O)O
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| InChi Key |
SUXNLHAGYIRFJQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/2C23H25N9O.3C4H6O4/c2*24-21-12-25-11-19(28-21)20-13-32-6-5-26-23(32)22(29-20)27-16-1-3-17(4-2-16)30-7-9-31(10-8-30)18-14-33-15-18;3*5-3(6)1-2-4(7)8/h2*1-6,11-13,18H,7-10,14-15H2,(H2,24,28)(H,27,29);3*1-2H2,(H,5,6)(H,7,8)
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| Chemical Name |
6-(6-aminopyrazin-2-yl)-N-[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]imidazo[1,2-a]pyrazin-8-amine;butanedioic acid
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| Synonyms |
GS-SYK; GS-9876; GS 9876; GS9876
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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: ~83.3 mg/mL (~134.3 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.35 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 (3.35 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6112 mL | 8.0562 mL | 16.1124 mL | |
| 5 mM | 0.3222 mL | 1.6112 mL | 3.2225 mL | |
| 10 mM | 0.1611 mL | 0.8056 mL | 1.6112 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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