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]。