TY - JOUR T1 - Danirixin: a reversible and selective antagonist of the CXC chemokine receptor 2. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.240705 SP - jpet.117.240705 AU - Jakob Busch-Petersen AU - Donald C. Carpenter AU - Miriam Burman AU - James Foley AU - Gerald E. Hunsberger AU - David J. Kilian AU - Michael Salmon AU - Ruth J. Mayer AU - John G. Yonchuk AU - Ruth Tal-Singer Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/06/13/jpet.117.240705.abstract N2 - 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 (pIC50) 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 Ca2+ mobilization assays, with a Kb of 6.5 nM and pA2 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 pIC50s 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 (LPS) or ozone challenge, with median effective doses (ED50s) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states where 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. ER -