Identification of novel chemotypes as CXCR2 antagonists via a scaffold hopping approach from a thiazolo[4,5-d]pyrimidine

The chemokine receptor CXCR2 and its ligands mediate neutrophil migration to the inflammation site, function as growth factors in many tumor cells and are involved in angiogenesis. Moreover, CXCR2 mediated recruitment of myeloid-derived suppressor cells results in tumor immunosuppression. Consequently, CXCR2 antagonism is a promising strategy for cancer immunotherapy and treatment of inflammatory disorders. Over a decade ago, several thiazolo[4,5- d ]pyrimidines were reported as potent CXCR2 antagonists. Optimization of this scaffold focused mainly on the ring substituents, while the aromatic core was mostly unexplored. In this study, a scaffold hopping strategy was applied to the unsubstituted thiazolo moiety. Fourteen novel bicyclic heteroaromatic and cycloaliphatic systems were prepared and evaluated for CXCR2 antagonism using binding and calcium mobilization assays. This study revealed that the triazolo[4,5- d ]pyrimidine, the isoxazolo[5,4- d ]pyrimidine and the pyrido[3,4- d ]pyrimidine scaffolds were endowed with IC 50 values below 1 μM in both assays and therefore are promising skeletons for further optimization. • CXCR2 is a promising drug target in immunology and oncology. • Scaffold hopping was applied starting from a thiazolo[4,5-d]pyrimidine scaffold. • Fourteen ring fused pyrimidine scaffolds were prepared as CXCR2 antagonists. • A triazolo[4,5-d]-, isoxazolo[4,5-d]- and pyrido[3,4-d]pyrimidine were most promising.