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 (Kd = 0.20 nM), rat (Kd = 0.20 nM), and cynomolgus monkey (Kd = 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC50 ∼3–6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (Kd = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC50 ∼1000 nM). Oral treatment with Sch527123 blocked pulmonary neutrophilia (ED50 = 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 (ED50 = 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED50 =<0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppressed the pulmonary neutrophilia (ED50 = 1.3 mg/kg), goblet cell hyperplasia (ED50 = 0.7 mg/kg), and increase in BAL mucin content (ED50 = <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 (ED50 = 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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.119040.
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ABBREVIATIONS: COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage; CINC, cytokine-induced neutrophil chemoattractant; Sch527123, 2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide; Sch-N, Sch527123; CXCL1, growth-related protein-α; CXCL5, epithelial-derived neutrophil attractant-78; CXCL7, neutrophil-activating peptide-2; CXCL8, interleukin-8; ELR, glutamine-leucine-arginine motif; i.t., intratracheal; LPS, lipopolysaccharide; MIP-2, macrophage inflammatory protein-2; PAS, periodic acid Schiff; V2O5, vanadium pentoxide; H&E, hematoxylin and eosin; ELISA, enzyme-linked immunosorbent assay; SB-332235, N-(2-hydroxy-3-sulfamyl-4-chlorophenyl)-N-(2,3-dichlorophenyl)urea.
- Received December 21, 2006.
- Accepted April 25, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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