The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site.