Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2

J Med Chem. 2014 Oct 23;57(20):8378-97. doi: 10.1021/jm500827t. Epub 2014 Oct 8.


The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure-activity studies that examined the effect of a novel series of S-substituted 6-mercapto-N-phenyl-nicotinamides on CXCL1-stimulated Ca(2+) flux in whole human PMNs led to the discovery of 2-[5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic acid (SX-517), a potent noncompetitive boronic acid CXCR1/2 antagonist. SX-517 inhibited CXCL1-induced Ca(2+) flux (IC50 = 38 nM) in human PMNs but had no effect on the Ca(2+) flux induced by C5a, fMLF, or PAF. In recombinant HEK293 cells that stably expressed CXCR2, SX-517 antagonized CXCL8-induced [(35)S]GTPγS binding (IC50 = 60 nM) and ERK1/2 phosphorylation. Inhibition was noncompetitive, with SX-517 unable to compete the binding of [(125)I]-CXCL8 to CXCR2 membranes. SX-517 (0.2 mg/kg iv) significantly inhibited inflammation in an in vivo murine model. SX-517 is the first reported boronic acid chemokine antagonist and represents a novel pharmacophore for CXCR1/2 antagonism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Binding, Competitive
  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacology
  • Chemokine CXCL1 / antagonists & inhibitors
  • Combinatorial Chemistry Techniques
  • HEK293 Cells / drug effects
  • Humans
  • Inflammation / drug therapy
  • Interleukin-8 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred Strains
  • Neutrophils / drug effects
  • Niacinamide / chemistry
  • Niacinamide / pharmacology*
  • Phosphorylation
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / metabolism
  • Structure-Activity Relationship


  • 2-(5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl)phenylboronic acid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Boronic Acids
  • CXCL1 protein, human
  • Chemokine CXCL1
  • Interleukin-8
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Niacinamide