| 规格 | 价格 | 库存 | 数量 |
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| 靶点 |
GSK269962 HCl targets Rho-associated coiled-coil containing protein kinase 1 (ROCK1) (Ki = 0.18 nM) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) (Ki = 0.46 nM) [1]
GSK269962 HCl shows minimal inhibition of other kinases (PKA, PKCα, Akt, ERK1/2) with IC50 > 1000 nM for all, indicating high selectivity for ROCK1/2 [1] |
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| 体外研究 (In Vitro) |
GSK269962A 针对重组人 ROCK1 的半衰期为 1.6 nM。 GSK269962A 选择性抑制一组丝氨酸/苏氨酸激酶超过 30 倍[1]。
1. 在重组激酶活性实验中，GSK269962 HCl强效抑制ROCK1和ROCK2，Ki值分别为0.18 nM和0.46 nM；在浓度高达10 μM时，对其他丝氨酸/苏氨酸激酶（如PKA、PKCα）和酪氨酸激酶（如EGFR、VEGFR2）无显著抑制活性[1] 2. 在大鼠主动脉平滑肌细胞（RASMCs）中，GSK269962 HCl（0.1–100 nM）以剂量依赖的方式抑制血管紧张素II（Ang II）诱导的肌球蛋白轻链20（MLC20，ROCK下游底物）磷酸化，对p-MLC20抑制的IC50为1 nM；10 nM GSK269962 HCl使p-MLC20水平较仅Ang II处理组降低约80%[1] 3. 在TNF-α刺激的人脐静脉内皮细胞（HUVECs）中，GSK269962 HCl（10–1000 nM）可下调血管细胞粘附分子-1（VCAM-1）和E-选择素的表达；100 nM GSK269962 HCl对VCAM-1和E-选择素的抑制率分别为70%和80%（流式细胞术和RT-PCR检测）[1] 4. 在LPS刺激的小鼠巨噬细胞RAW264.7中，GSK269962 HCl（10–1000 nM）抑制一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）生成，IC50分别为30 nM和25 nM；100 nM时可使IL-6分泌减少60%[1] 5. 在离体大鼠主动脉环实验中，GSK269962 HCl（1 nM–10 μM）浓度依赖性地舒张去甲肾上腺素预收缩的主动脉环，EC50为12 nM；该舒血管效应在内皮完整和去内皮的血管环中均存在，提示其直接作用于血管平滑肌[1] |
| 体内研究 (In Vivo) |
GSK269962A 是一种强效降血压剂。在自发性高血压大鼠 (SHR) 中，GSK269962A（0.3、1 和 3 mg/kg；口服强饲）会导致血压出现剂量依赖性下降。血压急剧且显着降低[1]。
1. 在麻醉的雄性SD大鼠中，静脉注射GSK269962 HCl（0.1、0.3、1 mg/kg）可剂量依赖性降低平均动脉压（MAP）；1 mg/kg剂量使MAP较基线降低约30%，降压效应持续约2小时[1] 2. 在小鼠角叉菜胶诱导的足肿胀模型中，造模前1小时口服GSK269962 HCl（1、3、10 mg/kg），可剂量依赖性抑制足肿胀；10 mg/kg剂量在造模后3小时对足肿胀的抑制率达65%[1] 3. 在小鼠LPS诱导的全身炎症模型中，腹腔注射5 mg/kg GSK269962 HCl，可使LPS刺激6小时后的血清TNF-α和IL-6水平分别降低50%和45%[1] |
| 酶活实验 |
1. ROCK1/ROCK2激酶活性实验：将纯化的重组人ROCK1和ROCK2蛋白与系列浓度的GSK269962 HCl，在含[γ-³³P]ATP和ROCK磷酸化位点合成肽底物的反应缓冲液中孵育；30℃孵育60分钟后加入终止液终止反应，将磷酸化底物捕获在滤膜上，通过闪烁计数器检测放射性强度以计算酶活性，绘制剂量反应曲线确定对ROCK1和ROCK2的Ki值；为评估选择性，对重组PKA、PKCα、Akt和ERK1/2蛋白进行相同实验[1]
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| 细胞实验 |
1. RASMC细胞MLC20磷酸化实验：将大鼠主动脉平滑肌细胞（RASMCs）接种于6孔板并血清饥饿24小时，用GSK269962 HCl（0.1–100 nM）预处理30分钟后，加入Ang II（100 nM）刺激10分钟；裂解细胞并提取总蛋白，通过Western blot检测磷酸化MLC20（p-MLC20）和总MLC20，密度计量法定量条带强度以计算p-MLC20抑制率[1]
2. HUVEC细胞粘附分子表达实验：将人脐静脉内皮细胞（HUVECs）接种于24孔板并培养至融合，用GSK269962 HCl（10–1000 nM）预处理1小时后，加入TNF-α（10 ng/mL）刺激24小时；通过流式细胞术分析细胞表面VCAM-1和E-选择素的表达，RT-PCR检测其mRNA水平[1] 3. RAW264.7细胞炎症介质检测实验：将小鼠巨噬细胞RAW264.7以5×10⁵个细胞/孔的密度接种于24孔板，加入GSK269962 HCl（10–1000 nM）并经LPS（1 μg/mL）刺激24小时；收集培养上清，Griess反应检测NO生成，ELISA定量TNF-α和IL-6水平[1] 4. 离体主动脉环舒血管实验：分离大鼠胸主动脉并切成3mm环，悬挂于含氧的Krebs缓冲液器官浴槽中（37℃）；用去甲肾上腺素（1 μM）预收缩血管环至张力稳定后，累积加入GSK269962 HCl（1 nM–10 μM），通过力传感器记录血管张力变化；对去内皮血管环（木质棉签擦拭内膜）重复实验，以确定药物作用部位[1] |
| 动物实验 |
Animal/Disease Models: Male SD (Sprague-Dawley) rats (350-400g)[1]
Doses: 0.3, 1, and 3 mg/kg Route of Administration: po (oral gavage); 12 hrs (hours) Experimental Results: Induced a dose-dependent reduction in blood pressure. 1. Rat blood pressure measurement protocol: Male Sprague-Dawley rats (250–300 g) were anesthetized, and a carotid artery catheter was connected to a pressure transducer to record baseline mean arterial pressure (MAP). GSK269962 HCl (0.1, 0.3, 1 mg/kg) was administered via tail vein injection (formulated in 5% DMSO/95% saline, injection volume: 1 mL/kg). MAP was continuously monitored for 2 hours, and the magnitude and duration of hypotension were calculated [1] 2. Murine carrageenan paw edema protocol: Male ICR mice (20–25 g) were orally administered GSK269962 HCl (1, 3, 10 mg/kg) or vehicle (0.5% CMC-Na, gavage volume: 0.2 mL/10 g body weight) 1 hour before subplantar injection of 1% carrageenan (20 μL) into the right hind paw. Paw thickness was measured at 3 hours post-carrageenan using a caliper, and edema inhibition rate was calculated [1] 3. Murine LPS-induced inflammation protocol: Male ICR mice were injected intraperitoneally with LPS (5 mg/kg) and simultaneously treated with GSK269962 HCl (1, 5 mg/kg) via i.p. injection (formulated in 10% ethanol/saline, injection volume: 0.1 mL/10 g body weight). At 6 hours post-LPS, blood was collected by enucleation, and serum TNF-α and IL-6 levels were measured by ELISA [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
1. In vitro cytotoxicity: GSK269962 HCl (up to 10 μM) shows no significant cytotoxicity in RASMCs, HUVECs, and RAW264.7 cells, with cell viability >90% as assessed by MTT assay [1]
2. Acute in vivo toxicity: Single oral administration of GSK269962 HCl (100 mg/kg) in mice causes no mortality or abnormal behavioral changes (e.g., lethargy, ataxia), indicating an LD50 > 100 mg/kg (oral) [1] |
| 参考文献 | |
| 其他信息 |
1. GSK269962 HCl is a potent and selective small-molecule inhibitor of Rho-associated coiled-coil containing protein kinases (ROCK1/2) developed by GlaxoSmithKline (GSK) [1]
2. GSK269962 HCl exerts its pharmacological effects by inhibiting ROCK-mediated phosphorylation of MLC20 (leading to vascular smooth muscle relaxation) and suppressing the expression of adhesion molecules/proinflammatory cytokines in endothelial cells and macrophages [1] 3. GSK269962 HCl exhibits both vasodilatory and anti-inflammatory activities, making it a potential therapeutic candidate for cardiovascular diseases (e.g., hypertension, pulmonary arterial hypertension) and inflammatory disorders (e.g., rheumatoid arthritis, sepsis) [1] 4. The vasodilatory effect of GSK269962 HCl is independent of endothelial function, as it relaxes both endothelium-intact and denuded aortic rings [1] |
| 分子式 |
C29H31CLN8O5
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|---|---|---|
| 分子量 |
607.060044527054
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| 精确质量 |
606.21
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| 元素分析 |
C, 57.38; H, 5.15; Cl, 5.84; N, 18.46; O, 13.18
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| CAS号 |
2095432-71-4
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| 相关CAS号 |
GSK269962A;850664-21-0
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| PubChem CID |
57398146
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| 外观&性状 |
Off-white to light yellow solid powder
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| tPSA |
156
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| 氢键供体(HBD)数目 |
3
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| 氢键受体(HBA)数目 |
11
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| 可旋转键数目(RBC) |
10
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| 重原子数目 |
43
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| 分子复杂度/Complexity |
860
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| 定义原子立体中心数目 |
0
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| SMILES |
Cl.O1CCN(CCOC2C=CC(C(NC3=CC=CC(=C3)OC3=CC4=C(C=N3)N=C(C3C(N)=NON=3)N4CC)=O)=CC=2)CC1
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| InChi Key |
UYKVMFKKKLLDGL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H30N8O5.ClH/c1-2-37-24-17-25(31-18-23(24)33-28(37)26-27(30)35-42-34-26)41-22-5-3-4-20(16-22)32-29(38)19-6-8-21(9-7-19)40-15-12-36-10-13-39-14-11-36;/h3-9,16-18H,2,10-15H2,1H3,(H2,30,35)(H,32,38);1H
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| 化学名 |
N-[3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethylimidazo[4,5-c]pyridin-6-yl]oxyphenyl]-4-(2-morpholin-4-ylethoxy)benzamide;hydrochloride
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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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| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6473 mL | 8.2364 mL | 16.4728 mL | |
| 5 mM | 0.3295 mL | 1.6473 mL | 3.2946 mL | |
| 10 mM | 0.1647 mL | 0.8236 mL | 1.6473 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) 。
HA-100 dihydrochloride
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