Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2

Abstract

CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca-mobilization assays, with a K (the concentration of antagonist that binds 50% of the receptor population) of 6.5 nM and antagonist potency (pA) of 8.44, and is fully reversible in washout experiments over 180 minutes. In rat and human whole-blood studies assessing neutrophil activation by surface CD11b expression following CXCL2 (rat) or CXCL1 (human) challenge, danirixin blocks the CD11b upregulation with pICs of 6.05 and 6.3, respectively. Danirixin dosed orally also blocked the influx of neutrophils into the lung in vivo in rats following aerosol lipopolysaccharide or ozone challenge, with median effective doses (EDs) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states in which neutrophils are increased in response to inflammation, such as pulmonary diseases. In comparison with navarixin, a CXCR2 antagonist from a different chemical class, the binding characterization of danirixin is distinct. These observations may offer insight into the previously observed clinical differences in induction of neutropenia between these compounds.

The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis

“…Targeting chemokine receptors, for instance CXCR2, which is important for neutrophil migration, may also be a therapeutic option (Figure 2). Danirixin, a selective and reversible antagonist of CXCR2, decreases the activation and transmigration of neutrophils to the lungs of rats treated with aerosolised lipopolysaccharide [139]. A clinical trial to evaluate the efficacy of Danirixin in RSV-infected infants <2 years of age (ClinicalTrials.gov identifier: NCT02201303) is ongoing.…”

CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin

“…We therefore hypothesised that in keeping with our in vivo results, we would observe heterogeneity in response to danirixin. Purified neutrophils from healthy donors were stimulated with CXCL-8 (10 ng•mL −1 ) or CXCL-1 (1000 nM); as previously reported [11], showing a significant increase in CD11b expression (figure 1b). Pre-treatment with danirixin (10 µM) significantly reduced CD11b activation by a mean±SD of 46.4±15.8%) in CXCL-8-treated cells ( paired t-test, p=0.0165) and 35.6±2.52% in CXCL-1-treated cells ( paired t-test, p=0.0187).…”

“…Danirixin has previously been shown to successfully block CXCL-1-induced CD11b upregulation as a marker of neutrophil activation [11,12,14], and so to understand the negative clinical results with danirixin, we replicated this in vitro. CXCL-8 is an inflammatory cytokine that has been previously shown to activate neutrophils and stimulate NET formation through activation of CXCR1 and, predominantly, CXCR2.…”

Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference

“…10.10. A randomized, double-blind, placebo controlled study to evaluate the safety, tolerability and clinical effect of oral Danirixin (GSK1325756) in the treatment of adults with acute, uncomplicated influenza (201682) Sumita Roy-Ghanta GSK, Philadelphia, Pennsylvania, USA Oral Danirixin (DNX) is a selective, competitive reversible inhibitor of CXC chemokine receptor 2 (CXCR2) (Busch-Petersen et al, 2017). CXCR2 is a key receptor in the chemotaxis of neutrophils to sites of inflammation.…”