Synthesis, Structure-Activity Relationship Studies, and ADMET Properties of 3-Aminocyclohex-2-en-1-ones as Chemokine Receptor 2 (CXCR2) Antagonists.

Herein we describe the synthesis and structure-activity relationships of 3-aminocyclohex-2-en-1-one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm. In silico ADMET prediction suggests that all active compounds possess drug-like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure-activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists.