生物活性
Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn's disease.
化学数据
| 分子量 | 425.5 |
| 分子式 | C21H23N5O3S |
| CAS号 | 1206161-97-8 |
| 纯度 | 98.65% |
| 溶解性（25°C） | DMSO 20 mg/mL |
| 储存和运输条件 | 固体粉末： -20°C 冷藏长期储存
常温运输及临时存放 |
实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）
| 细胞实验 |
|---|
| 细胞系 | T cells |
| 方法 | T cell differentiation studies.
PBMCs were isolated from buffy coats of healthy donors (Blood Transfusion Center, Red Cross, Leuven, Belgium) using density gradient centrifugation on Lymphoprep. Naive CD4+ T cells were further isolated by depletion of non–T helper and memory CD4+ T cells using a naive CD4+ T cell isolation kit II (Miltenyi Biotec). Isolated naive CD4+ T cells were stimulated with plate-bound anti-CD3 (3 μg/ml) and anti-CD28 (5 μg/ml) Abs in the presence of cytokines that drive differentiation into Th1, Th2, or Th17 Th subsets. For Th1 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IL-4 Ab (MAB204; R&D Systems), 10 ng/ml IL-2 (R&D Systems), and 10 ng/ml IL-12 (R&D Systems) (17). For Th2 cell polarization, cells were cultured in the presence of 10 μg/ml anti–IFN-γ Ab (Becton Dickinson), 25 ng/ml IL-4 (R&D Systems), and 10 ng/ml IL-2 (17). For Th17 cell polarization, a mix of the following cytokines was used: 10 ng/ml IL-6 (R&D Systems), 10 ng/ml IL-1β (R&D Systems), 1 ng/ml TGF-β (PeproTech), and 100 ng/ml IL-23 (R&D Systems) (18). To monitor effects of compounds on T cell differentiation, compounds were added at indicated concentrations at the start of T cell differentiation. After 5 d, RNA was extracted using an RNeasy Mini kit (Qiagen), reverse transcribed, and the extent of Th subset differentiation was monitored by determining expression of IFN-γ (Th1 marker), IL-13 (Th2 marker), or IL-17F (Th17 marker) using real-time PCR on the ViiA7 thermocycler with predesigned TaqMan Assay-on-Demand gene expression primer/probe sets (Applied Biosystems). Gene expression was normalized to 18S and expressed as ΔCt values, with ΔCt = Ctgene – Ct18S or expressed as relative mRNA level of specific gene expression as obtained using the 2–ΔCt method. |
| 浓度 | 10, 1, 0.1 or 0 μM |
| 处理时间 | 5 days |
| 动物实验 |
|---|
| 动物模型 | therapeutic rat CIA model |
| 配制 | 0.05 M acetic acid |
| 剂量 | 50 mg/kg twice daily for 14 d |
| 给药处理 | oral |
不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
储备液配制
以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.3502 mL | 11.7509 mL | 23.5018 mL |
| 5 mM | 0.47 mL | 2.3502 mL | 4.7004 mL |
| 10 mM | 0.235 mL | 1.1751 mL | 2.3502 mL |
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