Received for publication January 3, 2007.
Revised April 25, 2007.
Accepted for publication April 25, 2007.

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 is a potent, selective antagonist of the human CXCR1 and CXCR2 receptors (Gonsiorek et al, 2006). Here we describe its pharmacologic properties at rodent CXCR2 and at the CXCR1 and CXCR2 receptors in the cynomolgus monkey, and 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 (IC₅₀~3-6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (K_d=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 intra-nasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppressed the pulmonary neutrophilia (ED₅₀ = 1.8) and increase in bronchoalveolar lavage (BAL) mucin content (ED₅₀ = <0.1 mg/kg) induced by intra-tracheal (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.

Key words: CXCR1/2, Sch527123, antagonist, inflammation, neutrophils, pulmonary

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				W. Gonsiorek, X. Fan, D. Hesk, J. Fossetta, H. Qiu, J. Jakway, M. Billah, M. Dwyer, J. Chao, G. Deno, et al. Pharmacological Characterization of Sch527123, a Potent Allosteric CXCR1/CXCR2 Antagonist J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 477 - 485. [Abstract] [Full Text] [PDF]