1. Exploration of Pyrido[3,4-d]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2
- Author
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Max Van Hoof, Sandra Claes, Katrijn Boon, Tom Van Loy, Dominique Schols, Wim Dehaen, and Steven De Jonghe
- Subjects
Organic Chemistry ,Pharmaceutical Science ,pyrido[3,4-d]pyrimidines ,Analytical Chemistry ,SAR study ,Structure-Activity Relationship ,Pyrimidines ,Chemistry (miscellaneous) ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Humans ,Receptors, Chemokine ,Physical and Theoretical Chemistry ,CXCR2 antagonists - Abstract
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. ispartof: MOLECULES vol:28 issue:5 ispartof: location:Switzerland status: published
- Published
- 2023
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