JPE-1375
目录号 : GC68029JPE-1375 是一种补体 C5a 受体 1 (C5aR1) 拮抗剂。JPE-1375 能有效抑制小鼠体内多形核白细胞动员 (EC50=6.9 µM) 和降低 TNF 水平 (EC50=4.5 µM)。JPE-1375 可用于自身免疫性和炎性疾病的研究。
Cas No.:1254036-23-1
Sample solution is provided at 25 µL, 10mM.
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JPE-1375 is a complement C5a receptor 1 (C5aR1) antagonist. JPE-1375 effectively inhibits polymorphonuclear leukocyte mobilization (EC50=6.9 µM) and reduces TNF levels (EC50=4.5 µM) in mice. JPE-1375 can be used in studies of autoimmune and inflammatory diseases[1].
JPE-1375 (0.3, 1.0, 3.0 mg/kg; i.v.; single) inhibits PMN (polymorphonuclear leukocytes) mobilization and TNF with EC50 values of 6.9 and 4.5 µM, respectively[1].
JPE-1375 (1 mg/kg; i.v.; single) demonstrates a rapid distribution in the plasma, followed by elimination in mice[1].
JPE-1375 (1 mg/kg; i.v.; single) shows a strong negative correlation between PMN mobilization and TNF production with plasma concentrations[1].
Animal Model: | C57BL/6J wild-type (10 to 12-week-old; C5a pharmacodynamic model)[1]. |
Dosage: | 0.3, 1.0, 3.0 mg/kg |
Administration: | Intravenous injection; single. |
Result: | Significantly decreased C5a-mediated PMN mobilization at 1 and 3 mg/kg doses, while no effect was observed at a 0.3 mg/kg dose. Showed a significant reduction in TNF plasma levels at 1 and 3 mg/kg dose with both compounds reducing C5a-mediated TNF by about 90%. |
Animal Model: | C57BL/6J wild-type mice(10 to 12-week-old)[1]. | ||||||||||||||||||||||
Dosage: | 1 mg/kg | ||||||||||||||||||||||
Administration: | Intravenous injection; single. | ||||||||||||||||||||||
Result: |
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[1]. Cui CS, et al. In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy. ACS Pharmacol Transl Sci. 2021 Dec 21;5(1):41-51.
Cas No. | 1254036-23-1 | SDF | Download SDF |
分子式 | C49H63FN10O9 | 分子量 | 955.08 |
溶解度 | DMSO : 100 mg/mL (104.70 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.047 mL | 5.2352 mL | 10.4703 mL |
5 mM | 0.2094 mL | 1.047 mL | 2.0941 mL |
10 mM | 0.1047 mL | 0.5235 mL | 1.047 mL |
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给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy
ACS Pharmacol Transl Sci 2021 Dec 21;5(1):41-51.PMID:35059568DOI:PMC8762733
The complement C5a receptor 1 (C5aR1) has been studied as a potential therapeutic target for autoimmune and inflammatory diseases, with several drug candidates identified. Understanding the pharmacokinetics and pharmacodynamics of a drug candidate is a crucial preclinical step that allows for a greater understanding of a compound's in vivo biodistribution and target engagement to assist in clinical dose selection and dosing frequency. However, few in vivo pharmacodynamic methods have been described for C5a inhibitors. In this study, we, therefore, developed a complete in vivo pharmacodynamic assay in mice and applied this method to the peptide-based C5aR1 antagonists PMX53 and JPE-1375. Intravenous administration of recombinant mouse C5a induced rapid neutrophil mobilization and plasma TNF elevation over a 60 min period. By using C5a receptor-deficient mice, we demonstrated that this response was driven primarily through C5aR1. We next identified using this model that both PMX53 and JPE-1375 have similar in vivo working doses that can inhibit C5aR1-mediated neutrophilia and cytokine production in a dose as low as 1 mg/kg following intravenous injection. However, the in vivo active duration for PMX53 lasted for up to 6 h, significantly longer than that for JPE-1375 (<2 h). Pharmacokinetic analysis demonstrated rapid plasma distribution and elimination of both compounds, although PMX53 had a longer half-life, which allowed for the development of an accurate pharmacokinetic/pharmacodynamic model. Overall, our study developed a robust in vivo pharmacodynamic model for C5aR1 inhibitors in mice that may assist in preclinical translational studies of therapeutic drug candidates targeting C5a and its receptors.