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

Abstract

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.Combating inflammatory disease: New derivatives of 3‐aminocyclohex‐2‐en‐1‐ones were synthesized and evaluated for their CXCR2 inhibition. Structure– activity relationship studies of these compounds were performed. Several compounds display CXCR2 IC50 values less than 10 μm, and also show selectivity against CXCR2 and low cytotoxicity. In silico ADMET prediction suggests most active compounds possess good drug‐like properties.