Exploration of Pyrido[3,4- d ]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2.

Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-]pyrimidine analogue as a promising CXCR2 antagonist with an IC value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure-activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4-]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4-]pyrimidine analogue (compound ) that is endowed with similar antagonistic potency as the original hit.