Small-molecule ligands for the CXCR3 chemokine receptor receive considerable attention as a means to interrogate the roles of CXCR3 in vitro and in vivo and/or to potentially treat various conditions such as inflammatory diseases and cancer. We have synthesized and explored a novel class of small-molecule antagonists for CXCR3. A medium-throughput screen revealed an adamantane-guanidine as a hit. The guanidine unit was replaced by a small quaternary ammonium group, leading to ca. 5-fold increase in affinity. Substitution of the adamantane group by a myrtenyl moiety further increased affinity, while the benzyl group was decorated with an additional (substituted) aryl ring. This led to the identification of several bisaryl-based ligands with CXCR3 affinities of around 100 nM and with the ability to antagonize the functional activity of CXCL10. © 2011 Elsevier Ltd. All rights reserved.