title: Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2.
abstract: 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.
authors.affiliation: Syntrix Biosystems , 215 Clay Street, Auburn, Washington 98001, United States.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Maeda
authors.forename: Angela M
authors.initials: AM
authors.lastname: Peck
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schuler
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.forename: Winston N
authors.initials: WN
authors.lastname: Wicomb
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
authors.forename: John A
authors.initials: JA
authors.lastname: Zebala
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors; D020650:Combinatorial Chemistry Techniques; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000187:drug effects; D009536:Niacinamide / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000597473:2-(5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl)phenylboronic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001897:Boronic Acids; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D009536:Niacinamide