NBI-74330 is a high-affinity CXCR3 antagonist that inhibits the binding of CXCR3 to its ligands CXCL10 and CXCL11, reduces the formation of atherosclerotic plaques in LDL receptor-deficient mice, and decreases the migration of CD4+ T cells and macrophages to the peritoneum.

[125I]-CXCL11-CXCR3:3.2 nM (Ki, in CXCR3-CHO cell membranes), [125I]-CXCL10-CXCR3:1.5 nM (Ki, in CXCR3-CHO cell membranes)

Methods: DBA/1J mice were treated with NBI-74330 (100 mg/kg) in a collagen-induced arthritis (CIA) model. Arthritis scores and histopathological changes were assessed. Flow cytometry was used to investigate the effects of NBI-74330 on Th1 (IFN-γ, TNF-α, T-bet, STAT4, Notch-3, and RANKL), Th17 (IL-21, IL-17A, STAT3, and RORγt), and Th22 (IL-22) cell expression in splenic CD4 and CXCR3 T cells. RT-PCR was used to assess mRNA levels of IFN-γ, TNF-α, T-bet, RANKL, IL-17A, RORγt, and IL-22 in knee joint tissues. ELISA was used to measure serum protein levels of IFN-γ, TNF-α, and IL-17A. Results: The severity of arthritis scores and histological severity of inflammation were significantly reduced in NBI-74330-treated CIA mice. The percentages of CD4IFN-γ, CD4TNF-α, CD4T-bet, CD4STAT4, CD4Notch-3, CXCR3IFN-γ, CXCR3TNF-α, CXCR3T-bet, CXCR3STAT4, CXCR3Notch-3, CD4RANKL, CD4IL-21, CD4IL-17A, CD4STAT3, CD4RORγt, and CD4IL-22 cells were decreased in NBI-74330-treated CIA mice. In addition, NBI-74330 treatment downregulated the mRNA levels of IFN-γ, TNF-α, T-bet, RANKL, STAT3, IL-17A, RORγt, and IL-22. [1]