Structure–Activity Relationship of novel phenylacetic CXCR1 inhibitors

Diclofenac (1) significantly inhibited (IC50=12nM) the WT CXCR1/L1.2 cell migration induced by CXCL8 while the efficacy of 1 was completely lost in Lys99Ala CXCR1/L1.2 mutant (IC50 >10μM). We reported recently the Structure–Activity Relationship (SAR) of a class of CXCL8 allosteric modulators. They invariably share a 2-arylpropionic moiety so far considered a key structural determinant of the biological activity. We show the results of recent SAR studies on a novel series of phenylacetic derivatives supported by a combined approach of mutagenesis experiments and conformational analysis. The results suggest novel insights on the fine role of the propionic/acetic chain in the modulation of CXCL8 receptors.