Fasudil (HA-1077) HCl
(Synonyms: 盐酸法舒地尔; HA-1077 Hydrochloride; AT-877 Hydrochloride) 目录号 : GC14289
Fasudil (HA-1077) HCl（法舒地尔；HA-1077；AT877）是一种非特异性RhoA/ROCK抑制剂，对ROCK1的Ki为0.33μM，IC50为0.158μM，对ROCK2和PKA、PKC、PKG的IC50分别为4.58μM、12.30μM、1.650μM。
Cas No.:105628-07-7
Sample solution is provided at 25 µL, 10mM.
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Fasudil (HA-1077) HCl (HA-1077; AT877) is a non-specific RhoA/ROCK inhibitor with a Ki of 0.33μM and an IC50 of 0.158μM for ROCK1, and IC50 of 4.58μM, 12.30μM, and 1.650μM for ROCK2, PKA, PKC, and PKG, respectively[1]. The monomeric G protein RhoA and its activated target Rho kinase (ROCK) constitute the RhoA/ROCK signaling pathway, which has the function of inducing cytoskeletal reorganization, cell migration, and stress fiber formation, and also affects endothelial permeability, tissue compatibility, cell proliferation, and apoptosis[2, 3]. Fasudil (HA-1077) HCl is also an effective Ca2+ channel antagonist and vasodilator[4].
In vitro, Fasudil (HA-1077) HCl (0-30μM) treatment of human bladder cancer cell lines (5637 and UM-UC-3 cells) for 72h inhibited cell proliferation and migration in a dose-dependent manner, induced cell apoptosis, and significantly reduced the expression of ROCK-I and ROCK-II[5]. Fasudil (HA-1077) HCl (0.04, 0.2, 1μg/mL) pre-treated the co-culture system established by neutrophils and human pulmonary microvascular endothelial cells (HPMECs) for 30min, reduced neutrophil transendothelial cell migration, and inhibited neutrophil endothelial chemotaxis[6]. Fasudil (HA-1077) HCl (100μM) treatment of rat hepatic stellate cells and human hepatic stellate cell-derived TWNT-4 cells inhibited cell extension, stress fiber formation, and α-SMA expression, stimulated the production and transcription of matrix metalloproteinase-1 (MMP-1), and enhanced collagenase activity[7].
In vivo, Fasudil (HA-1077) HCl (10mg/kg) was intravenously administered to mice after myocardial ischemia/reperfusion injury, inhibiting c-Jun N-terminal kinase (JNK)-mediated apoptosis-inducing factor (AIF) translocation and reducing cardiomyocyte apoptosis during ischemia/reperfusion[8].
References:
[1] Chen M, Liu A, Ouyang Y, et al. Fasudil (HA-1077) HCl and its analogs: a new powerful weapon in the long war against central nervous system disorders?[J]. Expert opinion on investigational drugs, 2013, 22(4): 537-550.
[2] Crosas-Molist E, Samain R, Kohlhammer L, et al. Rho GTPase signaling in cancer progression and dissemination[J]. Physiological Reviews, 2022, 102(1): 455-510.
[3] Radeva M Y, Waschke J. Mind the gap: mechanisms regulating the endothelial barrier[J]. Acta physiologica, 2018, 222(1): e12860.
[4] Chen Y, Yuan T, Zhang H, et al. Fasudil (HA-1077) HCl evokes vasodilatation of rat mesenteric vascular bed via Ca2+ channels and Rho/ROCK pathway[J]. European journal of pharmacology, 2016, 788: 226-233.
[5] Abe H, Kamai T, Hayashi K, et al. The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells[J]. BMC cancer, 2014, 14: 1-12.
[6] Wang J, Xu J, Zhao X, et al. Fasudil (HA-1077) HCl inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2[J]. Experimental cell research, 2018, 365(1): 97-105.
[7] Fukushima M, Nakamuta M, Kohjima M, et al. Fasudil (HA-1077) HCl hydrochloride hydrate, a Rho‐kinase (ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells[J]. Liver international, 2005, 25(4): 829-838.
[8] Zhang J, Li X X, Bian H J, et al. Inhibition of the activity of Rho-kinase reduces cardiomyocyte apoptosis in heart ischemia/reperfusion via suppressing JNK-mediated AIF translocation[J]. Clinica Chimica Acta, 2009, 401(1-2): 76-80.
Fasudil (HA-1077) HCl（法舒地尔；HA-1077；AT877）是一种非特异性RhoA/ROCK抑制剂，对ROCK1的Ki为0.33μM，IC50为0.158μM，对ROCK2和PKA、PKC、PKG的IC50分别为4.58μM、12.30μM、1.650μM[1]。单体G蛋白RhoA及其激活靶点Rho激酶（ROCK）组成了RhoA/ROCK信号通路，该通路具有诱导细胞骨架重组、细胞迁移和应力纤维形成功能，还影响内皮通透性、组织相容性、细胞增殖、细胞凋亡等[2, 3]。Fasudil (HA-1077) HCl也是一种有效的Ca2+通道拮抗剂和血管扩张剂[4]。
在体外，Fasudil (HA-1077) HCl（0-30μM）处理人膀胱癌细胞系（5637和UM-UC-3细胞）72h，均以剂量依赖性方式抑制了细胞增殖和迁移，诱导了细胞凋亡，显著降低了ROCK-I和ROCK-II的表达[5]。Fasudil (HA-1077) HCl（0.04、0.2、1μg/mL）预处理中性粒细胞和人肺微血管内皮细胞（HPMECs）建立的共培养系统30min，减少了中性粒细胞跨内皮细胞迁移，抑制了中性粒细胞内皮趋化性[6]。Fasudil (HA-1077) HCl（100μM）处理大鼠肝星状细胞和人肝星状细胞来源的TWNT-4细胞，抑制了细胞伸展、应力纤维的形成和α-SMA的表达，刺激基质金属蛋白酶-1（MMP-1）的产生和转录，并增强胶原酶活性[7]。
在体内，Fasudil (HA-1077) HCl（10mg/kg）通过静脉注射治疗心脏缺血/再灌注损伤后的小鼠，抑制了c-Jun氨基末端激酶（JNK）介导的凋亡诱导因子（AIF）转位，减少了缺血再灌注时心肌细胞凋亡[8]。
| Cell experiment [1]: | |
Cell lines | 5637 cells、UM-UC-3 cells |
Preparation Method | 5637 cells and UM-UC-3 cells (5×104/well) were seeded into 96-well plates in serum-containing medium and were allowed to attach for 24h. Then the medium was removed and replaced with new medium containing 0, 1, 10, 30μM of Fasudil (HA-1077) HCl. After being cultured for 72h, the cells were incubated with 50μL of MTT(5mg/mL) for 1h. The formazan product was dissolved in 100 mL of DMSO and its absorbance was measured at a wavelength of 630nm in a microplate reader. Proliferation of 5637 cells and UM-UC-3 cells was also assessed by quantitative ELISA. |
Reaction Conditions | 0, 1, 10, 30μM; 72h |
Applications | Fasudil (HA-1077) HCl inhibits the proliferation of 5637 cells and UM-UC-3 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Female Wistar rats |
Preparation Method | Five experimental groups were studied. 1.sham operation. (n=30); 2.left anterior descending branch(LAD) was occluded for 30 min and reperfused for 180min plus administration of normal saline(NS)[1ml normal saline i.v. 1h before operation] (n=18); 3.LAD was occluded for 30min and reperfused for 180min plus administration of Fasudil (HA-1077) HCl, inhibitor of Rho-kinase[10mg/kg i.v. 1h before operation. Fasudil (HA-1077) HCl was dissolved in 1ml normal saline] (n=18); 4.LAD was occluded for 30min and reperfused for 180min plus administration of SP600125, inhibitor of JNK[6mg/kg i.p. 2h before operation. SP600125 was dissolved in 100µl DMSO] (n=12); 5.LAD was occluded for 30min and reperfused for 180min plus administration of DMSO[100µl DMSO i.p. 2h before operation.] (n=12). |
Dosage form | 10mg/kg; i.v. |
Applications | Fasudil (HA-1077) HCl reduced cell apoptosis in I/R in vivo via suppression of c-Jun N-terminal kinase(JNK)-mediated apoptosis-inducing factor(AIF) translocation. |
References: | |
| Cas No. | 105628-07-7 | SDF | |
| 别名 | 盐酸法舒地尔; HA-1077 Hydrochloride; AT-877 Hydrochloride | ||
| 化学名 | 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline;hydrochloride | ||
| Canonical SMILES | C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3.Cl | ||
| 分子式 | C14H17N3O2S.HCl | 分子量 | 327.83 |
| 溶解度 | ≥ 16.4mg/mL in DMSO, ≥ 4.81 mg/mL in EtOH with ultrasonic, ≥ 50 mg/mL in Water | 储存条件 | Store at 4°C |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0504 mL | 15.2518 mL | 30.5036 mL |
| 5 mM | 610.1 μL | 3.0504 mL | 6.1007 mL |
| 10 mM | 305 μL | 1.5252 mL | 3.0504 mL |
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