title: SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans.
abstract: BACKGROUND
  Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans.
  
  
  CONCLUSIONS
  SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects.
  
  
  OBJECTIVE
  To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects.
  
  
  METHODS
  Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers.
  
  
  RESULTS
  Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses.
  
  
  CONCLUSIONS
  SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.
authors.affiliation: COPD Clinical Discovery, GlaxoSmithKline, King of Prussia, PA, USA. aili.l.lazaar@gsk.com
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Sweeney
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: MacDonald
authors.forename: Neil E
authors.initials: NE
authors.lastname: Alexis
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001991:Bronchitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D039481:CD11b Antigen / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000276:immunology*; D010126:Ozone / Q000009:adverse effects*; D009195:Peroxidase / Q000378:metabolism; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016037:Single-Blind Method; D013183:Sputum / Q000201:enzymology; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D039481:CD11b Antigen; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; C568923:SB 656933; D013449:Sulfonamides; D010126:Ozone; D009195:Peroxidase