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.