Exploration of Pyrido[3,4-<i>d</i>]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2
Max Van Hoof,
Sandra Claes,
Katrijn Boon,
Tom Van Loy,
Dominique Schols,
Wim Dehaen,
Steven De Jonghe
Affiliations
Max Van Hoof
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Sandra Claes
Department of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium
Katrijn Boon
Department of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium
Tom Van Loy
Department of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium
Dominique Schols
Department of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium
Wim Dehaen
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Steven De Jonghe
Department of Microbiology, Immunology and Transplantation—Laboratory of Virology and Chemotherapy, KU Leuven—Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium
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-d]pyrimidine analogue as a promising CXCR2 antagonist with an IC50 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-d]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-d]pyrimidine analogue (compound 17b) that is endowed with similar antagonistic potency as the original hit.
