PT  - JOURNAL ARTICLE
AU  - Chapman, Richard W.
AU  - Minnicozzi, Michael
AU  - Celly, Chander S.
AU  - Phillips, Jonathan E.
AU  - Kung, Ted T.
AU  - Hipkin, R. William
AU  - Fan, Xuedong
AU  - Rindgen, Diane
AU  - Deno, Gregory
AU  - Bond, Richard
AU  - Gonsiorek, Waldemar
AU  - Billah, Motasim M.
AU  - Fine, Jay S.
AU  - Hey, John A.
TI  - A Novel, Orally Active CXCR1/2 Receptor Antagonist, Sch527123, Inhibits Neutrophil Recruitment, Mucus Production, and Goblet Cell Hyperplasia in Animal Models of Pulmonary Inflammation
AID  - 10.1124/jpet.106.119040
DP  - 2007 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 486--493
VI  - 322
IP  - 2
4099  - http://jpet.aspetjournals.org/content/322/2/486.short
4100  - http://jpet.aspetjournals.org/content/322/2/486.full
SO  - J Pharmacol Exp Ther2007 Aug 01; 322
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics