title: A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation.
abstract: Sch527123 [2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]ben-zamide] is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al., 2007). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, as well as its in vivo activity in models demonstrating prominent pulmonary neutrophilia, goblet cell hyperplasia, and mucus production. Sch527123 bound with high affinity to the CXCR2 receptors of mouse (K(d) = 0.20 nM), rat (K(d) = 0.20 nM), and cynomolgus monkey (K(d) = 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC(50) approximately 3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K(d) = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC(50) approximately 1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED(50) = 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED(50) = 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED(50) =<0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED(50) = 1.3 mg/kg), goblet cell hyperplasia (ED(50) = 0.7 mg/kg), and increase in BAL mucin content (ED(50) = <1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduced the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED(50) = 0.3 mg/kg). Therefore, Sch527123 may offer benefit for the treatment of inflammatory lung disorders in which pulmonary neutrophilia and mucus hypersecretion are important components of the underlying disease pathology.
authors.affiliation: Schering Plough Research Institute, Pulmonary and Peripheral Neurobiology, Kenilworth, NJ 07033, USA. richard.chapman@spcorp.com
authors.forename: Richard W
authors.initials: RW
authors.lastname: Chapman
authors.forename: Michael
authors.initials: M
authors.lastname: Minnicozzi
authors.forename: Chander S
authors.initials: CS
authors.lastname: Celly
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Phillips
authors.forename: Ted T
authors.initials: TT
authors.lastname: Kung
authors.forename: R William
authors.initials: RW
authors.lastname: Hipkin
authors.forename: Xuedong
authors.initials: X
authors.lastname: Fan
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: Gregory
authors.initials: G
authors.lastname: Deno
authors.forename: Richard
authors.initials: R
authors.lastname: Bond
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Motasim M
authors.initials: MM
authors.lastname: Billah
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: John A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D001991:Bronchitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001999:Bronchoscopy; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019743:Chemokines, CXC / Q000032:analysis / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003503:Cyclobutanes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D020397:Goblet Cells / Q000473:pathology*; D006965:Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000032:analysis / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017968:Vanadium Compounds / Q000494:pharmacology
chemical_list: C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D019743:Chemokines, CXC; C513294:Cxcl3 protein, rat; D003503:Cyclobutanes; D008070:Lipopolysaccharides; D009077:Mucins; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D017968:Vanadium Compounds; C066075:vanadium pentoxide