The CXC chemokine receptor 2 (CXCR2) mediates chemotaxis of leukocytes and controls the extravasation and activation of neutrophils. Danirixin is a small-molecule, selective, and reversible CXCR2 antagonist[2]. Danirixin competes with CXCL8 binding to the membranes prepared from Chinese hamster ovary cells transfected with human CXCR2 or CXCR1 with IC50 values of 12.5nM (pIC50 = 7.90 ± 0.04) and 977nM (pIC50 = 6.03 ± 0.05), respectively. It also acts as a competitive antagonist against CXCL8 in Ca2+ mobilization assays with a Kb of 6.5nM and a pA2 of 8.44. Oral administration of Lewis rats with danirixin at doses of 0.3, 3, and 30mg/kg increased the EC50 value for CXCL2-induced CD11b expression in neutrophils from 4.5nM (the vehicle-treated group) to 9.4, 11.9, and 38.1nM, respectively. In fasted rats following inhaled lipopolysaccharide challenge, danirixin at a dosage of 10 mg/kg led to 84% inhibition of neutrophil influx to the lung with an ED50 value of 1.4mg/kg. In fed rats, 10mg/kg of danirixin resulted in 64% inhibition with an ED50 value of 2.3 mg/kg. Danirixin also dose-dependently inhibited neutrophils when administered to fasted rats 1 hour prior to ozone exposure with an ED50 value of 16.0 mg/kg[3].
Danirixin/达尼利星 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
Colorectal cancer model established with CT26 cells
Oral gavage
15 mg/kg
Every two days until the completion of the study
In vivo treatment with danirixin (antagonists of CXCR2) promoted tumor progression in animal models established with CT26 cells. CXCR2 antagonism may function via an immune component, with CXCR2 antagonist treatment in mice resulting in reduced activated DCs and correlating with decreased Interferon gamma (IFN-g) or Granzyme B expressed CD8+ T cells.
搜索
