A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H-4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo. 1-[(5-chloro-1H-indol-2-yl) carbonyl]-4-methylpiperazine (JNJ 7777120) has a K-i of 4.5 nM versus the human receptor and a pA(2) of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H-1, H-2, or H-3 receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of similar to30% in rats and 100% in dogs, with a half-life of similar to3 h in both species. JNJ 7777120 blocks histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. In addition, it can block the histamine-induced migration of tracheal mast cells from the connective tissue toward the epithelium in mice. JNJ 7777120 significantly blocks neutrophil infiltration in a mouse zymosan-induced peritonitis model. This model is reported to be mast cell-dependent, which suggests that the compound effect may be mediated by mast cells. These results indicate that the histamine H-4 receptor plays a role in the inflammatory process. Selective H-4 receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.