Development of a systemically-active dual CXCR1/CXCR2 allosteric inhibitor and its efficacy in a model of transient cerebral ischemia in the rat.

The chemokine receptors CXCR1 and CXCR2 present on polymorphonuclear neutrophils (PMN), bind the chemokine CXC ligand 8 (CXCL8)/interleukin-8 (IL-8), and have a key role in PMN recruitment in inflammation. Based on the structure of reparixin, a small-molecular-weight allosteric inhibitor of CXCR1, we designed a dual inhibitor of CXCR1 and CXCR2 with a longer in vivo half-life, DF2156A. This molecule inhibited human and rat PMN migration in response to CXCR1 and CXCR2 ligands and showed an elimination half-life following i.v. administration, of 19 hours. In a rat model of cerebral ischemia/reperfusion induced by temporary (90 min) middle cerebral artery (MCA) occlusion, DF2156A (8 mg-kg, i.v., at the time of reperfusion) decreased the PMN infiltrate, infarct size and significantly improved neurological function. These results indicate that CXCR1/CXCR2 and their ligands have a role in the inflammatory component of cerebral ischemia, and that these pathways represent an important pharmacological target.