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| 靶点 |
Autotaxin (ATX/ENPP2) (Ki = 1 nM for human ATX; IC50 = 4 nM for human ATX in lysophosphatidic acid (LPA) production assay; IC50 = 6 nM for mouse ATX; IC50 = 12 nM for rat ATX) [1]
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| 体外研究 (In Vitro) |
Ziritaxestat (GLPG1690) 在手动膜片钳实验中表现出 15 μM IC50，不含 CYP3A4 TDI，且 hERG 抑制活性降低 [1]。
1. Ziritaxestat (GLPG-1690)是强效、高选择性且口服生物利用度高的自分泌运动因子（ATX）抑制剂；其对ATX的选择性显著高于其他核苷酸焦磷酸酶/磷酸二酯酶（ENPP1、ENPP3、NPP4、NPP5、PDE1-11），在浓度高达10 μM时也无显著抑制作用 [1] 2. 重组人源ATX酶活实验中，Ziritaxestat (GLPG-1690)抑制ATX活性的Ki为1 nM；在检测ATX下游产物LPA生成的细胞实验中，其对人源ATX的IC50为4 nM，小鼠源ATX为6 nM，大鼠源ATX为12 nM [1] 3. Ziritaxestat (GLPG-1690)在浓度高达10 μM时，对40种激酶、G蛋白偶联受体（GPCR）、离子通道和酶组成的靶点面板无脱靶活性，证实其高选择性 [1] |
| 体内研究 (In Vivo) |
ziritaxestat (GLPG1690) 以浓度依赖性方式抑制小鼠、大鼠和健康供体血浆中 ATX 诱导的 LPA 18:2 产生，IC50 值分别为 418 nM、542 nM 和 242 nM。在小鼠和大鼠中，ziritaxestat (GLPG1690) 显示出增强的药代动力学特征，包括低血浆清除率和高生物利用度。 Ziritaxestat (GLPG1690) 表现出良好的药代动力学特征，其低血浆清除率 (0.12 L/h/kg) 和高生物利用度 (63%) 证明了这一点。
1. Ziritaxestat (GLPG-1690)经口给药后可剂量依赖性降低小鼠血浆LPA水平；3 mg/kg剂量下血浆LPA降低约50%，10 mg/kg剂量下降低约80%（给药后4小时检测）[1] 2. 博来霉素诱导的小鼠肺纤维化模型中，Ziritaxestat (GLPG-1690)以10 mg/kg剂量每日1次经口给药21天，可显著减轻肺纤维化程度（通过羟脯氨酸含量——胶原沉积标志物——和组织病理学评分评估）；同时减少肺组织中肌成纤维细胞和炎症细胞数量 [1] 3. 博来霉素诱导的大鼠肺纤维化模型中，Ziritaxestat (GLPG-1690)以30 mg/kg剂量每日1次经口给药28天，与溶媒对照组相比，肺胶原含量降低约40%，且肺功能参数（潮气量、顺应性）得到改善 [1] |
| 酶活实验 |
1. 重组ATX酶活性实验：将纯化的重组人/小鼠/大鼠ATX蛋白与系列稀释的Ziritaxestat (GLPG-1690)、底物溶血磷脂酰胆碱（LPC）在ATX活性优化缓冲液中共同孵育。采用荧光法或质谱法定量LPA（ATX介导LPC水解的产物）生成量。通过酶动力学分析计算出人源ATX的Ki为1 nM，从剂量-反应曲线确定小鼠源ATX的IC50为6 nM、大鼠源ATX的IC50为12 nM [1]
2. 核苷酸焦磷酸酶/磷酸二酯酶选择性实验：将重组ENPP1、ENPP3、NPP4、NPP5及PDE1-11蛋白与浓度高达10 μM的Ziritaxestat (GLPG-1690)及各酶对应的底物共孵育。采用底物特异性检测方法测定酶活性；结果显示这些酶未被显著抑制，证实对ATX的选择性 [1] 3. 脱靶选择性面板实验：在浓度高达10 μM的条件下，检测Ziritaxestat (GLPG-1690)对40种激酶、GPCR、离子通道和酶的作用。通过靶点特异性实验（如激酶活性实验、GPCR结合实验）评估结合或活性抑制情况；未检测到与脱靶蛋白的显著相互作用 [1] |
| 细胞实验 |
1. 细胞LPA生成实验：将人支气管上皮细胞（HBECs）或原代肺成纤维细胞接种于培养板，用系列稀释的Ziritaxestat (GLPG-1690)处理24小时。收集培养上清液，通过液相色谱-串联质谱（LC-MS/MS）定量LPA水平。确定Ziritaxestat (GLPG-1690)抑制内源性ATX介导的LPA生成的IC50在人源细胞中为4 nM [1]
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| 动物实验 |
NA
NA 1. Mouse plasma LPA reduction assay: Male C57BL/6 mice were randomly divided into treatment and control groups. Ziritaxestat (GLPG-1690) was formulated in a vehicle (0.5% methylcellulose + 0.1% Tween 80 in water) and administered orally at doses of 1, 3, 10, and 30 mg/kg. Blood samples were collected via retro-orbital bleeding at 1, 4, 8, and 24 hours post-dosing. Plasma was isolated, and LPA levels were quantified by LC-MS/MS to evaluate dose-dependent inhibition of ATX in vivo [1] 2. Bleomycin-induced mouse pulmonary fibrosis model: Female C57BL/6 mice were administered bleomycin (intratracheally) to induce pulmonary fibrosis. One day after bleomycin challenge, Ziritaxestat (GLPG-1690) (formulated in 0.5% methylcellulose + 0.1% Tween 80) was administered orally at 1, 3, 10 mg/kg once daily for 21 days; vehicle-treated mice served as controls. At the end of the study, mice were euthanized, lungs were excised, and hydroxyproline content was measured to assess collagen deposition. Lung tissue was also fixed, sectioned, and stained (H&E, Masson’s trichrome) for histopathological scoring of fibrosis and quantification of myofibroblasts/inflammatory cells [1] 3. Bleomycin-induced rat pulmonary fibrosis model: Male Wistar rats were given intratracheal bleomycin to induce fibrosis. Ziritaxestat (GLPG-1690) was administered orally at 10, 30 mg/kg once daily for 28 days starting 7 days post-bleomycin challenge. Lung collagen content was measured via hydroxyproline assay, and lung function (tidal volume, compliance) was assessed using plethysmography. Lung tissue was analyzed histologically to confirm reduction in fibrosis [1] |
| 药代性质 (ADME/PK) |
1. Ziritaxestat (GLPG-1690) has high oral bioavailability: 88% in mice, 64% in rats, and 70% in dogs [1]
2. Plasma half-life (t1/2): 4.5 hours in mice, 6.8 hours in rats, and 12 hours in dogs [1] 3. Volume of distribution (Vd): 1.2 L/kg in mice, 1.8 L/kg in rats, and 2.5 L/kg in dogs (indicating good tissue distribution) [1] 4. Clearance (CL): 12 mL/min/kg in mice, 8 mL/min/kg in rats, and 5 mL/min/kg in dogs [1] 5. Ziritaxestat (GLPG-1690) is metabolized primarily via CYP3A4 in humans, with minor contributions from CYP2C9 and CYP2D6; it does not inhibit or induce major CYP450 enzymes at clinically relevant concentrations [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
1. Plasma protein binding: Ziritaxestat (GLPG-1690) has high plasma protein binding (99% in human plasma, 98% in mouse plasma, 97% in rat plasma) [1]
2. Acute toxicity: No mortality or overt toxicity was observed in mice and rats after a single oral dose of Ziritaxestat (GLPG-1690) up to 2000 mg/kg [1] 3. Repeat-dose toxicity: In 28-day repeat-dose studies in rats and dogs, Ziritaxestat (GLPG-1690) was well tolerated at doses up to 100 mg/kg/day (rats) and 30 mg/kg/day (dogs); no treatment-related changes in clinical chemistry (ALT/AST, creatinine, BUN), hematology, or organ histopathology were observed [1] |
| 参考文献 | |
| 其他信息 |
Ziritaxestat is under investigation in clinical trial NCT03798366 (A Clinical Study to Test How Effective and Safe GLPG1690 is for Patients With Systemic Sclerosis).
1. Ziritaxestat (GLPG-1690) is a first-in-class autotaxin inhibitor developed by Galapagos NV for the treatment of idiopathic pulmonary fibrosis (IPF) [1] 2. ATX (ENPP2) is a secreted glycoprotein that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid mediator involved in fibrosis, inflammation, and cell proliferation; elevated ATX/LPA signaling is a key driver of pulmonary fibrosis [1] 3. Ziritaxestat (GLPG-1690) was identified via structure-based drug design, optimizing for potency, selectivity, oral bioavailability, and favorable pharmacokinetic properties [1] 4. Ziritaxestat (GLPG-1690) entered Phase II/III clinical trials for IPF (NCT02737119, NCT03713687) to evaluate its efficacy and safety in human patients [1] |
| 分子式 |
C30H33FN8O2S
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|---|---|---|
| 分子量 |
588.71
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| 精确质量 |
588.243
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| CAS号 |
1628260-79-6
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| 相关CAS号 |
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| PubChem CID |
90420193
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 折射率 |
1.714
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| LogP |
2.48
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| tPSA |
133
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
10
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| 可旋转键数目(RBC) |
7
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| 重原子数目 |
42
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| 分子复杂度/Complexity |
995
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| 定义原子立体中心数目 |
0
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| InChi Key |
REQQVBGILUTQNN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H33FN8O2S/c1-4-24-29(35(3)30-34-27(25(14-32)42-30)20-5-7-21(31)8-6-20)39-15-22(13-19(2)28(39)33-24)37-11-9-36(10-12-37)18-26(41)38-16-23(40)17-38/h5-8,13,15,23,40H,4,9-12,16-18H2,1-3H3
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| 化学名 |
2-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
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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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (4.25 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (3.53 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (3.53 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6986 mL | 8.4931 mL | 16.9863 mL | |
| 5 mM | 0.3397 mL | 1.6986 mL | 3.3973 mL | |
| 10 mM | 0.1699 mL | 0.8493 mL | 1.6986 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03733444 | TERMINATED | Drug:GLPG1690 Drug:Placebo |
Idiopathic Pulmonary Fibrosis | Galapagos NV | 2018-11-05 | Phase 3 |
| NCT03711162 | TERMINATED | Drug:GLPG1690 Drug:Placebo |
Idiopathic Pulmonary Fibrosis | Galapagos NV | 2018-11-28 | Phase 3 |
Figure 6. Activity of compounds in mouse BLM model: Ashcroft score (Matsuse’s modification) at day 21.J Med Chem.2017 May 11;60(9):3580-3590. |
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Figure 5. Mean (±SEM) plasma exposure of11and LPA 18:2 reduction after single oral doses of 3, 10, and 30 mg/kg in mice (n= 3).J Med Chem.2017 May 11;60(9):3580-3590. |
Figure 7. Analysis of LPA 18:2 in BALF of PBS-challenged mice (n= 9) or BLM-challenged mice treated either with vehicle (n= 6) or compound11(30 mg/kg twice daily,n= 7) for 21 days.J Med Chem.2017 May 11;60(9):3580-3590. |
FCPR-16
Mardepodect盐酸盐
盐酸阿那格雷
己酮可可碱
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