Designing small molecule CXCR3 antagonists

Introduction: By virtue of its specificity for chemokines induced in Th1-associated pathologies, CXCR3 has attracted considerable attention as a target for therapeutic intervention. Several pharmacologically distinct small molecules with in vitro and in vivo potency have been described in the literature, although to date, none have shown efficacy in clinical trials. Areas covered: In this article, the author outlines the rationale for targeting CXCR3 and discusses the potential pitfalls in targeting receptors in poorly understood areas of chemokine biology. Furthermore, they cover emerging therapeutic areas outside of the traditional' Th1 arena in which CXCR3 antagonists may ultimately bear fruit. Finally, they discuss the design of recently discovered small molecules targeting CXCR3. Expert opinion: CXCR3 and its ligands appear to play roles in a multitude of diverse diseases in humans. In vitro studies suggest that CXCR3 is inherently 'druggable' and that potent, efficacious small molecules targeting CXCR3 antagonists will find a clinical niche. However, the well-trodden path to failure of small molecule chemokine receptor antagonists in clinical trials suggests that a cautious approach should be undertaken. Ideally, unequivocal evidence elucidating the precise role of CXCR3 should be obtained before targeting the receptor in a particular disease cohort.