R112
目录号 : GC33874
A Syk inhibitor
Cas No.:575474-82-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
R112 is an inhibitor of spleen tyrosine kinase (Syk; IC50 = 226 nM in cultured human mast cells) that acts in an ATP-competitive and reversible manner (Ki = 96 nM).1 It inhibits mast cell and basophil degranulation induced by anti-IgE cross-linking (EC50s = 353 and 280 nM, respectively). It also inhibits basophil degranulation induced by an allergen with an EC50 value of 490 nM. R112 inhibits the production of leukotriene C4 and decreases cytokine levels in cultured human mast cells.
1.Rossi, A.B., Herlaar, E., Braselmann, S., et al.Identification of the Syk kinase inhibitor R112 by a human mast cell screenJ. Allergy Clin. Immunol.118(3)749-755(2006)
| Cas No. | 575474-82-7 | SDF | |
| Canonical SMILES | FC1=CN=C(NC2=CC(O)=CC=C2)N=C1NC3=CC(O)=CC=C3 | ||
| 分子式 | C16H13FN4O2 | 分子量 | 312.3 |
| 溶解度 | DMSO : ≥ 41 mg/mL (131.28 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.202 mL | 16.0102 mL | 32.0205 mL |
| 5 mM | 0.6404 mL | 3.202 mL | 6.4041 mL |
| 10 mM | 0.3202 mL | 1.601 mL | 3.202 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias
Neuron 2022 Apr 20;110(8):1304-1317.PMID:PMC9035117DOI:10.1016/j.neuron.2022.03.004.
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel "ApoE Cascade Hypothesis" in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment
J Allergy Clin Immunol 2005 Apr;115(4):791-6.PMID:15806000DOI:10.1016/j.jaci.2005.01.040.
Background: R112 inhibits Syk kinase, a transducer of signaling through the Fcepsilon receptor of mast cells, blocking mast cell responses to allergic stimuli. Objective: Examine the efficacy and safety of intranasal R112 in volunteers with symptomatic seasonal allergic rhinitis compared with a placebo in a park setting. Methods: In this double-blind, placebo-controlled study of 319 volunteers with seasonal allergic rhinitis, 160 were randomized to intranasal R112 and 159 to a vehicle control during 2 days at 2 separate locations in spring 2004. Subjects were evaluated for symptoms of allergic rhinitis (i.e., sneezes, runny nose/sniffles, itchy nose, stuffy nose) on the basis of a possible maximum score of 32 for the Global Symptom Complex (GSC) scale. The primary outcome evaluated was the difference in the reduction in GSC (area under the curve over a period of 8 hours) from baseline between R112 and vehicle placebo. Results: At baseline, the combined GSC was approximately 18/32 and equal between treatment groups. After 8 hours (dosing 3 mg/nostril every 4 hours x 2), R112 significantly reduced the GSC compared with placebo (7 vs 5.4 units, respectively; P = .0005). Each individual symptom combined to form the GSC was also significantly improved in the R112 group compared with control ( P < .05). As early as 45 minutes after dosing, R112 showed a significant improvement in symptoms over placebo, and the duration of action exceeded 4 hours. Adverse effects were indistinguishable between the groups and clinically insignificant. Conclusion: Intranasal R112 was effective in this park study and is a promising new treatment for seasonal allergic rhinitis.
Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases
Expert Opin Investig Drugs 2022 Mar;31(3):291-303.PMID:35130124DOI:10.1080/13543784.2022.2040014.
Introduction: Autoimmune diseases (ADs) are disorders induced by multiple inflammatory mediators, in which immune system attacks healthy tissues and triggers tissue injury. Targeted regulation of the activity of kinases that influence inflammation is one of the major therapies for ADs. Recently, investigational spleen tyrosine kinase (SYK) inhibitors have shown encouraging results in the AD therapy. Areas covered: This article provides a background on autoimmune diseases and provides an update on investigational SYK inhibitors. This literature review was conducted by searching publications about investigational SYK inhibitors in the treatment of ADs from experimental to clinical studies. The search terms used were SYK inhibitors, R406, fostamatinib (R788), P505-15 (PRT062607), entospletinib (GS-9973), R112, lanraplenib (GS-9876), cerdulatinib, R343, BAY-61-3606, GSK compound 143 (GSK143), R211, SKI-G-618, SKI-O-85, ER-27319, YM193306, RO9021 in conjunction with autoimmune disease using electronic databases including PubMed, EMBASE, MEDLINE and Google Scholar. Expert opinion: SYK inhibitors are promising drugs with unique advantages and acceptable tolerability and safety for the treatment of ADs. However, the difficulties in developing highly selective SYK inhibitors and the unknown effects are challenges. Long-term and real-world data are essential to determine the risk-benefit ratio and true role of SYK inhibitors in the therapy of ADs.
Mast cell inhibitor R112 is well tolerated and affects prostaglandin D2 but not other mediators, symptoms, or nasal volumes in a nasal challenge model of allergic rhinitis
Allergy Asthma Proc 2006 May-Jun;27(3):208-13.PMID:16913263DOI:10.2500/aap.2006.27.2861.
Understanding of the role played by mast cells in allergic rhinitis (AR) has led to the development of novel therapies. The aim of this study was to determine the safety and tolerability of R112, an inhibitor of the tyrosine kinase Syk, in an allergen challenge model of AR. We also examined the effects of R112 on symptoms, mediator release, and nasal airway volumes. This double-blinded, randomized, placebo-controlled, crossover trial enrolled 20 out-of-season volunteers with AR. One intranasal dose of R112 or vehicle was administered and followed by an allergen challenge. In addition to safety monitoring, symptoms; changes in histamine, tryptase, and prostaglandin D2 (PGD2) content of nasal secretions; and acoustic rhinometry were determined over a 15-minute period. R112 was well tolerated. Adverse events were similar between treatments. Five minutes after allergen instillation, PGD2 was decreased when subjects received R112 compared with vehicle (93.4 +/- 23.0 pg/mL versus 171.6 +/- 23.0 pg/mL; p = 0.03), and this correlated with rhinorrhea (p = 0.05). However, at 10 minutes, changes in PGD2, tryptase, and histamine were not significant (46.8 +/- 9.2 pg/mL versus 68.6 +/- 9.2 pg/mL, p = 0.1; 9.5 +/- 2.7 ng/mL versus 16.6 +/- 2.9 ng/mL, p = 0.09; and 1.5 +/- 1.6 ng/mL versus 3.5 +/- 1.6 ng/mL, p = 0.4). No differences were found in symptoms or in acoustic rhinometry between treatment groups. Single-dose R112 appears safe and significantly reduces PGD2 but not histamine or tryptase release in response to allergen challenge in subjects with AR.
Identification of the Syk kinase inhibitor R112 by a human mast cell screen
J Allergy Clin Immunol 2006 Sep;118(3):749-55.PMID:16950297DOI:10.1016/j.jaci.2006.05.023.
Background: Activation of the IgE receptor, FcvarepsilonRI, in mast cells is the key mechanism initiating and propagating pathophysiological responses in allergic rhinitis. Objective: Identify and characterize a small molecule inhibitor of IgE-dependent mast cell activation for the treatment of allergic diseases. Methods: A cell-based high-throughput screen for small molecules that block IgE signaling was performed in cultured human mast cells. A potent inhibitor, referred to as R112, was selected and characterized by using biochemical and cell-based assays. R112 effects on IgE-dependent degranulation and cytokine production was measured in mast cells and basophils and compared with other mast cell inhibitors. Results: R112 inhibited degranulation induced by anti-IgE cross-linking in mast cells (tryptase release, effective concentration for 50% inhibition [EC(50)] = 353 nmol/L) or basophils (histamine release, EC(50) = 280 nmol/L), and by allergen (dust mite) in basophils (histamine release, EC(50) = 490 nmol/L). R112 also blocked leukotriene C4 production and all proinflammatory cytokines tested. Subsequent molecular characterization indicated that R112 is an ATP-competitive spleen tyrosine kinase (Syk) inhibitor (inhibitory constant [K(i)] = 96 nmol/L). Its onset of action was immediate, and the inhibition was reversible. Incubation of mast cells with R112 showed that cytokine production in mast cells was dependent on sustained activation of the FcvarepsilonRI-Lyn-spleen tyrosine kinase pathway. Unlike other mast cell inhibitors, R112 was able to completely inhibit all three IgE-induced mast cell functions: degranulation, lipid mediator production, and cytokine production. Conclusion: R112 potently, completely, and rapidly abrogated all mast cell activation cascades triggered by IgE receptor cross-linking. Clinical implications: R112 and its analogues offer a new modality in the treatment of allergic rhinitis.