Setipiprant is a selective and orally available prostaglandin D2 receptor 2 (DP2, also known as CRTH2) antagonist, which is a γ-carboline derivative with an IC₅₀ of 6nM[1]. As a G protein-coupled receptor, the DP2 receptor is mainly expressed on the surface of immune cells such as eosinophils and Th2 cells, and is involved in regulating allergic inflammatory responses, immune cell migration, and cytokine release[2]. By specifically blocking the DP2 receptor, Setipiprant has shown significant anti-inflammatory effects in models of inflammatory diseases such as allergic asthma and atopic dermatitis[3].
In vitro, when hESC cells are treated with Setipiprant (1-10μM) for 10 minutes, the compound inhibits PGD₂-induced eosinophil activation and shape change by blocking the CRTH2 receptor[1].
In vivo, after intravenous injection of Setipiprant (2mg/kg) in rats and dogs, relevant bioavailability data indicate that the compound exhibits good oral bioavailability and excellent pharmacokinetic properties in both animal species[1]. In addition, Setipiprant (1%) can effectively inhibit the activities of rat lens aldose reductase and kidney aldose reductase[4].
References:
[1] Fretz H, Valdenaire A, Pothier J, et al. Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist. Journal of Medicinal Chemistry 2013, 56(12):4899-4911.
[2] Kupczyk M, Kuna P Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives. Drugs 2017, 77(12):1281-1294.
[3] Strasser DS, Farine H, Holdener M, et al. Development of a decision-making biomarker for CRTH2 antagonism in clinical studies. New Horizons in Translational Medicine 2015, 2(4):118-125.
[4] Ballekova J, Soltesova-Prnova M, Majekova M, et al. Does inhibition of aldose reductase contribute to the anti-inflammatory action of setipiprant? Physiol Res 2017, 66(4):687-693.
Setipiprant是一种选择性、口服可用的前列腺素D2受体2（DP2，也称为CRTH2）拮抗剂，是γ-咔啉衍生物，其IC₅₀为6nM[1]。DP2受体作为一种G蛋白偶联受体，主要表达于嗜酸性粒细胞、Th2细胞等免疫细胞表面，参与调控过敏性炎症反应、免疫细胞迁移及细胞因子释放等过程[2]。Setipiprant通过特异性阻断DP2受体，在过敏性哮喘、特应性皮炎等炎症性疾病模型中显示出显著的抗炎功效[3]。
在体外，使用Setipiprant（1-10μM）处理hESC细胞10分钟，该化合物通过阻断CRTh2 受体，抑制PGD₂诱导的嗜酸性粒细胞活化及形状改变[1]。
在体内，使用Setipiprant（2mg/kg）对大鼠和犬进行静脉注射后，相关生物利用度数据表明，该化合物在这两种动物中均展现出良好的口服生物利用度及优异的药代动力学特性[1]。此外，Setipiprant（1%）能有效抑制大鼠晶状体醛糖还原酶和肾脏醛糖还原酶活性[4]。