Optimization of triazolo[4,5-d]pyrimidines towards human CC chemokine receptor 7 (CCR7) antagonists

CCR7 signaling directs the migration of both immune cells and Cancer cells to the lymph nodes, is involved in numerous chronic inflammatory disorders and lymph node metastases. Despite the therapeutic promise of CCR7 antagonists, no potent and selective small molecule CCR7 antagonists have been reported to date. Since most human chemokine G protein-coupled receptors (GPCRs) share a conserved intracellular allosteric binding site, new CCR7 Antagonist chemotypes may be identified by screening small molecules that are known to target this site in other chemokine GPCRs. In this work, our previously prepared series of 14 scaffold-modified analogues of a known thiazolo[4,5-d]pyrimidine CXCR2 Antagonist were screened as potential CCR7 antagonists. This resulted in the discovery of a triazolo[4,5-d]pyrimidine analogue with an IC₅₀ of 2.43 μM against CCR7 and 0.66 μM against CXCR2. Exploration of the structure-activity relationship (SAR) for the 3-, 5- and 7-position substituents of this triazolo[4,5-d]pyrimidine resulted in improved potency and selectivity, with an IC₅₀ of 0.43 μM and 11.02 μM against CCR7 and CXCR2, respectively, for the most selective derivative. Molecular docking showed that the binding mode of these triazolo[4,5-d]pyrimidines in CCR7 and CXCR2 corresponds with those of previously co-crystallized ligands.

1,2,3-triazolo[4,5-d]pyrimidine; CCR7 antagonist; CXCR2 antagonist; Hit finding; SAR optimization.