SCH79797 dihydrochloride is a highly potent and selective nonpeptide protease activated receptor 1 (PAR1) antagonist. It inhibits the binding of a high-affinity thrombin receptor-activating peptide to PAR1 with an IC50 of 70 nM and a Ki of 35 nM. SCH79797 dihydrochloride also inhibits thrombin-induced platelet aggregation with an IC50 of 3 μM. Moreover, it has antiproliferative and pro-apoptotic effects, and limits myocardial ischemia/reperfusion injury in rat hearts. Additionally, SCH79797 dihydrochloride potently prevents PAR1 activation in vascular smooth muscle cells, endothelial cells, and astrocytes[1][2][3][4].
体内研究
SCH79797 (2.5-250 μg/kg; intravenous injection; male Sprague Dawley rats) immediately before or during ischemia reduces myocardial necrosis following I/R in the intact rat heart in two rat models of myocardial ischemia/reperfusion (I/R) injury. This response is dose-dependent, with the optimal dose being 25 μg/kg[4].
体外研究
SCH79797 inhibits high-affinity thrombin receptor-activating peptide ([3H]haTRAP) binding in a competitive manner. It also inhibits α-thrombin- and haTRAP-induced aggregation of human platelets, while not inhibiting human platelet aggregation induced by other agonists. Furthermore, SCH79797 effectively inhibits the transient increases in cytosolic free Ca2+ concentration ([Ca2+]i) in hCASMC induced by thrombin. Additionally, it completely inhibits Thrombin- and TK-stimulated [3H]thymidine incorporation[1].
SCH79797 is capable of interfering with the growth of several human and mouse cell lines in a concentration-dependent manner. It exhibits ED50 values of 75 nM, 81 nM, and 116 nM for growth inhibition in NIH 3T3, HEK 293, and A375 cells, respectively. In NIH 3T3 cells, SCH79797 inhibits serum-stimulated activation of p44/p42 mitogen-activated protein kinases (MAPK) at low concentrations and induces apoptosis at higher concentrations[2].
SCH79797 2HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
P815 mouse mast cells
1.0 µM
16 hours
To evaluate the effect of SCH79797 (PAR1 inhibitor) on thrombin-induced mediator secretion from P815 cells. Results showed that SCH79797 reduced the secretion of VEGF, TNF-α, CCL-2, CXCL-5, and CXCL-1 but had no significant effect on IL-2 and IL-6 secretion.
Mediators Inflamm. 2019 Nov 14;2019:4952131
Human cardiomyocytes
10 µM
16 hours
SCH79797 attenuated thrombin-induced COX-2 expression and PGE2 production by inhibiting PAR1-dependent signaling pathways.
Br J Pharmacol. 2014 Oct;171(19):4504-19
E. coli MJF455
1 µM
16-17 hours
Evaluate the effect of SCH-79797 on bacterial growth, showing MscL expression-dependent growth inhibition
Antibiotics (Basel). 2022 Jul 19;11(7):970
Neural stem cells (NSCs)
35 or 70 nM
18 hours
SCH79797 promoted BrdU incorporation in PAR1+/+ NSCs, increasing proliferation by 39%.
Sci Rep. 2018 Jun 19;8(1):9360
Human tracheal smooth muscle cells (HTSMCs)
10 µM
1-hour pretreatment
SCH79797 significantly inhibited thrombin-induced upregulation of COX-2 mRNA levels and promoter activity
Mediators Inflamm. 2022 Apr 19;2022:4600029
Human umbilical vein endothelial cells (HUVECs)
150 nM
1-hour pretreatment, followed by 90 min hourseat stress and 6 or 12 hours recovery period
To investigate the effect of SCH79797 on heat stress-induced apoptosis in HUVECs. Results showed that SCH79797 significantly reduced cell apoptosis, caspase-3 activity, and expression of pro-apoptotic protein Bax, while increasing expression of anti-apoptotic protein Mcl-1.
Mol Med Rep. 2017 May;15(5):2595-2603
S. aureus MRSA USA300
6.3 μg/mL
2 hours
To evaluate efficacy against persister cells, SCH-79797 effectively killed persister cells
Cell. 2020 Jun 25;181(7):1518-1532.e14.
Cardiac fibroblasts
1 µM
2.5 hours
Inhibited ERK1/2 phosphorylation induced by thrombin or FXa
J Am Heart Assoc. 2020 Jun 16;9(12):e015616
E. coli lptD4213
6.2 μg/mL
3 hours
To assess bactericidal activity of SCH-79797, results showed significant reduction in colony forming units
Cell. 2020 Jun 25;181(7):1518-1532.e14.
Human neutrophils
10 µM
3 hours
Enhanced neutrophil killing of E. coli by increasing NET formation
J Antimicrob Chemother. 2018 Jun 1;73(6):1586-1594
Mouse neutrophils
10 µM
3 hours
Enhanced neutrophil killing of E. coli by increasing ROS production, NET formation, and CRAMP release
J Antimicrob Chemother. 2018 Jun 1;73(6):1586-1594
HEK293 cells
0.3 or 1 µM
3, 6, or 24 hours
Assessed cytotoxicity and apoptosis effects of SCH79797, showing no significant impact
Assess the effect of SCH-79797 on MscL channel activity via patch clamp, showing significant increase in channel activity
Antibiotics (Basel). 2022 Jul 19;11(7):970
SW480 cells
100 µM
48 hours
Attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells
Cell Death Dis. 2021 Sep 22;12(10):860
RKO cells
100 µM
48 hours
Attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells
Cell Death Dis. 2021 Sep 22;12(10):860
Oligodendrocyte progenitor cells (OPCs)
70 nM
48 hours
Inhibited PLP and MBP expression, reduced NogoA RNA levels
Glia. 2015 May;63(5):846-59
Human platelets
3 µM
5 min
Block PAR1, inhibit platelet aggregation and intracellular calcium signaling
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):216-20
SCH79797 2HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rat
Intraventricular hemorrhage model
Intracerebroventricular injection
0.15 nmol
Single injection, euthanized after 24 hours
To evaluate the inhibitory effect of SCH79797 on thrombin-induced hydrocephalus. Results showed that SCH79797 significantly reduced thrombin-induced ventricular enlargement and ventricular wall damage.
J Cereb Blood Flow Metab. 2014 Mar;34(3):489-94
Mice
PAR1−/− and PAR1+/+ mice
Bilateral intra-amygdala injection
1 µM
Single injection, lasting 15 minutes
To investigate the effect of SCH79797 on fear memory, results showed that pharmacological inhibition of PAR1 enhanced fear memory.
Mol Psychiatry. 2013 Oct;18(10):1136-45
Neonatal rat pups
Germinal matrix hemorrhage model
Intraperitoneal injection
10 mg/kg
Twice a day for three days
To evaluate the effects of PAR-1 antagonist SCH79797 on long-term neurofunctional and brain morphological outcomes after germinal matrix hemorrhage. Results showed that SCH79797 alone did not significantly improve neurofunctional recovery or reduce ventricular dilation and white matter loss.
Significantly improved survival, reduced lung injury and inflammation, and enhanced bacterial clearance
J Antimicrob Chemother. 2018 Jun 1;73(6):1586-1594
BALB/c nude mice
Xenograft model and metastasis model
Intraperitoneal injection
25 µg/mg
Once daily for 25 days
Reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model
Cell Death Dis. 2021 Sep 22;12(10):860
C57BL/6J mice
Pilocarpine-induced status epilepticus model
Intraperitoneal injection
25 mg/kg
Single dose, observed for 24 hours
To evaluate the effect of SCH79797 on LTP in a pilocarpine-induced status epilepticus model, results showed that SCH79797 prevented the reduction of LTP
Front Cell Neurosci. 2022 May 24;16:900925
Adult male Wistar rats
Lithium-pilocarpine induced status epilepticus model
Intraperitoneal injection
25 μg/kg
Once daily for 10 consecutive days
To evaluate the effect of PAR1 inhibition on animal survival, neuronal survival, epileptiform activity, and behavioral seizures post-SE. Results showed that SCH79797 significantly reduced mortality, decreased neuronal loss, and suppressed epileptiform activity and behavioral seizures.
Neurobiol Dis. 2015 Jun;78:68-76
Sprague-Dawley rats
Subarachnoid hemorrhage model
Intraperitoneal injection
25 μg/kg
Assessed at 24 hours
SCH79797 significantly reduced brain edema, Evans blue extravasation, and neurobehavioral deficits, and decreased PAR-1 expression while maintaining VE-cadherin levels
Stroke. 2013 May;44(5):1410-7
Sprague Dawley rats
Myocardial ischemia/reperfusion injury model
Intravenous injection
25 μg/kg
Single dose, 15 minutes before ischemia or during ischemia
To evaluate the protective effect of SCH79797 in vivo on myocardial ischemia/reperfusion injury, results showed that 25 μg/kg IV dose significantly reduced infarct size.
Basic Res Cardiol. 2007 Jul;102(4):350-8
Sprague Dawley rats
Intraventricular thrombin-induced hydrocephalus model
Intraperitoneal injection
25 μg/kg
Immediate administration, lasting for 24 hours
Inhibition of PAR1 attenuated thrombin-induced hydrocephalus and reversed the downregulation of VE-cadherin
CNS Neurosci Ther. 2019 Oct;25(10):1142-1150
Japanese white rabbits
Transient global cerebral ischemia/reperfusion injury model induced by cardiac arrest
Intravenous injection
25 μg/kg
Administered 10 minutes after restoration of spontaneous circulation and again 24 hours later
SCH79797 mitigates brain injury via anti-inflammatory and anti-apoptotic effects, possibly by modulating the ERK, JNK/c-Jun and PI3K/Akt pathways.
Neural Regen Res. 2017 Feb;12(2):242-249
Rats
Trigeminal neuralgia model
Intraperitoneal injection
25 μg/kg
Once a week
SCH79797 effectively ameliorated orofacial mechanical allodynia in the trigeminal neuralgia model
Front Mol Neurosci. 2022 Dec 20;15:1059980
Mice
Renin-overexpressing hypertensive mouse model
Continuous subcutaneous infusion
25 μg/kg/day
For 4 weeks
SCH79797 significantly reduced cardiac hypertrophy and fibrosis in Ren-Tg mice, decreased monocyte/macrophage deposition, and downregulated the expression of inflammatory and fibrotic-related genes
J Am Heart Assoc. 2020 Jun 16;9(12):e015616
Rats
Gastric ulcer model
Oral
5 nmol
Twice daily for 1 week
Significantly retard gastric ulcer healing
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):216-20
Sprague-Dawley rats
Surgical brain injury model
Intraperitoneal injection
5 or 25 μg/kg
Single dose, evaluated after 24 hours
SCH79797 reduced SBI-induced brain edema and neurological deficits, and decreased apoptosis by inhibiting the PAR-1/Ask1/JNK pathway.
Neurobiol Dis. 2013 Feb;50:13-20
Sprague-Dawley rats
Spinal cord injury (SCI) model
Intrathecally
50 μg/kg
Single injection, observed for 21 days
To evaluate the effect of SCH79797 on motor function recovery after SCI, results showed SCH79797 significantly reduced microglia/macrophage migration and improved motor function.
Neural Regen Res. 2023 Jun;18(6):1339-1346
Galleria mellonella
G. mellonella infection model
Injection
67 μg/larva
Single dose, survival rate observed
To assess antibiotic activity in an animal model, results showed significant prolongation of survival in infected wax worms
搜索
