SCH 79797 dihydrochloride
目录号 : GC10291
SCH 79797 dihydrochloride是一种高效的、具有选择性的非肽类蛋白酶激活受体 1（PAR1）拮抗剂，其IC50值为70nM，Ki值为35nM。
Cas No.:1216720-69-2
Sample solution is provided at 25 µL, 10mM.
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SCH 79797 dihydrochloride is an efficient and selective non-peptide proteinase-activated receptor 1 (PAR1) antagonist, with an IC50 of 70nM and a Ki of 35nM [1]. PAR1 is critically involved in the co-activation of coagulation and inflammatory responses [2]. SCH 79797 dihydrochloride has anti-proliferative and pro-apoptotic effects, and it can effectively prevent the activation of PAR 1 in vascular smooth muscle cells, endothelial cells, and astrocytes [3].
In vitro, SCH 79797 dihydrochloride (0-200nM) can interfere with the growth of various human and mouse cell lines in a concentration-dependent manner. The ED50 values of SCH 79797 dihydrochloride for inhibiting the growth of NIH3T3, HEK293 and A375 cells were 75nM, 81nM and 116nM, respectively. In NIH 3T3 cells, SCH 79797 dihydrochloride inhibits serum-stimulated p44/p42 mitogen-activated protein kinase (MAPK) activation at low concentrations and induces apoptosis at high concentrations [3]. Through metabolomics analysis of Escherichia coli NCM3722 treated with SCH 79797 dihydrochloride (13.9μg/mL) for 15 minutes, the level of DHFR substrate 7,8-dihydrofolate (DHF) in the cells increased approximately 10-fold, while the levels of folate metabolites downstream of DHF significantly decreased [4].
In vivo, by intravenously injecting SCH 79797 dihydrochloride (2.5, 10, 25, 50, 100, and 250μg/kg) 15 minutes before ischemia in rats, SCH 79797 dihydrochloride dose-dependently reduced myocardial necrosis after complete rat heart I/R, with the optimal dose being 25μg/kg [5]. By continuous subcutaneous injection of SCH 79797 dihydrochloride (25μg/kg/d) for 4 weeks, the thickness of the interventricular septum and left ventricular posterior wall of Ren-Tg mice, as well as the area of cardiac fibrosis and mononuclear cell/macrophage deposition, were significantly reduced. At the same time, SCH 79797 dihydrochloride inhibited the increased mRNA expression levels of PAR-1, TNF-α, TGF-β1, and COL 3A 1 in the mouse heart [6].
References:
[1] Ahn HS, Foster C, Boykow G, Stamford A, Manna M, Graziano M. Inhibition of cellular action of thrombin by N3-cyclopropyl-7-[[4-(1-methylethyl)phenyl]methyl]-7H-pyrrolo[3, 2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist. Biochem Pharmacol. 2000 Nov 15;60(10):1425-34.
[2] Schoergenhofer C, Schwameis M, Gelbenegger G, et al. Inhibition of protease-activated receptor (PAR1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia[J]. Thrombosis and haemostasis, 2018, 118(07): 1176-1184.
[3] Di Serio C, Pellerito S, Duarte M, Massi D, Naldini A, Cirino G, Prudovsky I, Santucci M, Geppetti P, Marchionni N, Masotti G, Tarantini F. Protease-activated receptor 1-selective antagonist SCH79797 inhibits cell proliferation and induces apoptosis by a protease-activated receptor 1-independent mechanism. Basic Clin Pharmacol Toxicol. 2007 Jul;101(1):63-9.
[4] Martin JK 2nd, Sheehan JP, Bratton BP, et al. A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance. Cell. 2020;181(7):1518-1532.e14.
[5] Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JE. SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. Basic Res Cardiol. 2007 Jul;102(4):350-8.
[6] Yokono Y, Hanada K, Narita M, et al. Blockade of PAR‐1 signaling attenuates cardiac hypertrophy and fibrosis in renin‐overexpressing hypertensive mice[J]. Journal of the American Heart Association, 2020, 9(12): e015616.
SCH 79797 dihydrochloride是一种高效的、具有选择性的非肽类蛋白酶激活受体 1（PAR1）拮抗剂，其IC50值为70nM，Ki值为35nM [1]。PAR1在凝血反应和炎症反应的协同激活过程中起着至关重要的作用[2]。SCH 79797 dihydrochloride具有抗增殖和促凋亡作用，还可有效阻止血管平滑肌细胞、内皮细胞和星形胶质细胞中的PAR1活化 [3] 。
在体外，SCH 79797 dihydrochloride（0-200nM）能够以浓度依赖性方式干扰多种人类和小鼠细胞系的生长。SCH 79797 dihydrochloride对NIH3T3、HEK293和A375细胞生长抑制的ED50分别为75nM、81nM和116nM。在NIH3T3细胞中，SCH 79797 dihydrochloride在低浓度下抑制血清刺激的p44/p42丝裂原活化蛋白激酶 (MAPK) 活化，并在高浓度下诱导细胞凋亡[3] 。通过SCH 79797 dihydrochloride（13.9μg/mL）处理15分钟后大肠杆菌NCM3722的代谢组学分析，细胞中DHFR底物7,8-二氢叶酸（DHF）的水平上升了大约10倍，而DHF下游的叶酸代谢物水平显著下降[4]。
在体内，通过在大鼠缺血前15分钟静脉推注SCH 79797 dihydrochloride（2.5, 10, 25, 50, 100和250μg/kg），SCH 79797 dihydrochloride剂量依赖性的减少了完整大鼠心脏I/R后的心肌坏死，最佳剂量为25μg/kg [5]。通过连续皮下注射SCH 79797 dihydrochloride（25μg/kg/d）治疗4周，显著降低了Ren‐Tg小鼠的室间隔和左心室后壁厚度以及心脏纤维化面积和单核细胞/巨噬细胞沉积 。同时SCH 79797 dihydrochloride抑制了小鼠心脏PAR-1、TNF-α、TGF-β1和COL 3A 1的mRNA表达水平的升高[6]。
| Cell experiment [1]: | |
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Cell lines |
NIH 3T3、HEK 293 and A375 cells |
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Preparation Method |
All cell lines were seeded at a low density (4×10^4 cells per well) in 6-well plate clusters. The next day, the cells were washed three times with PBS and then starved in serum-free DMEM medium for 24h. The next day, the medium was replaced with DMEM medium supplemented with 10% FBS, which contained gradually increasing concentrations of SCH 79797 dihydrochloride or a separate solvent (DMSO). When the cells were stimulated by growth factors, they were starved in serum-free DMEM medium for 24h; the next day, 25ng/ml of FGF2 or 30ng/ml of PDGF was added to the medium. When using FGF2 for stimulation, heparin (10U/ml) was added to the medium. When studying the effect of cell density on SCH79797-mediated growth inhibition, proliferation experiments were conducted according to the above method. Three independent growth experiments for each cell type were performed to calculate the ED50. |
|
Reaction Conditions |
0-200nM; 1-9 days |
|
Applications |
The ED50 for growth inhibition was 75nM, 81nM and 116nM for NIH 3T3, HEK 293 and A375 cells. Starting from a concentration of 200nM, SCH 79797 dihydrochloride induced a significant amount of cell death within the first 3 days in all cultures. |
| Animal experiment [2]: | |
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Animal models |
Male Sprague Dawley rats with myocardial I/R injury |
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Preparation Method |
The experiment employed a live-anesthetized rat model. The experiment followed the routine surgical operation procedures and the infarction area was measured. For the study of the infarction area, 6 rats were selected. They first underwent 30 minutes of local ischemia, followed by 180 minutes of reperfusion. In another series of experiments (a total of 6 rats), intravenous injection of SCH 79797 dihydrochloride was initiated 15 minutes before or after the onset of ischemia, and lasted for 1 minute. |
|
Dosage form |
2.5, 10, 25, 50, 100, and 250μg/kg；i.v. |
|
Applications |
SCH 79797 dihydrochloride administered immediately before or during ischemia reduced myocardial necrosis after I/R in intact rats. This response was dose-dependent, with the optimal dose being 25μg/kg. |
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References: |
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| Cas No. | 1216720-69-2 | SDF | |
| 化学名 | (Z)-N-(1-imino-7-(4-isopropylbenzyl)-1H-pyrrolo[3,2-f]quinazolin-3(2H,4H,7H)-ylidene)cyclopropanamine dihydrochloride | ||
| Canonical SMILES | CC(C1=CC=C(CN2C=CC3=C2C=CC(N/C4=N/C5CC5)=C3C(N4)=N)C=C1)C.Cl.Cl | ||
| 分子式 | C23H25N5.2HCl | 分子量 | 444.41 |
| 溶解度 | DMF: 5 mg/ml,DMSO: 11 mg/ml,DMSO:PBS(pH 7.2) (1:2): 0.33 mg/ml,Ethanol: 1 mg/ml | 储存条件 | Store at 2-8°C, protect from light |
| 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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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2502 mL | 11.2509 mL | 22.5017 mL |
| 5 mM | 0.45 mL | 2.2502 mL | 4.5003 mL |
| 10 mM | 0.225 mL | 1.1251 mL | 2.2502 mL |
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