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INFLAMMATION AND IMMUNOPHARMACOLOGY

A Potent and Selective Histamine H₄ Receptor Antagonist with Anti-Inflammatory Properties

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, California

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H₄ 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 pA₂ of 8.1. It is equipotent against the human, mouse, and rat receptors. It exhibits at least 1000-fold selectivity over H₁, H₂, or H₃ receptors and has no cross-reactivity against 50 other targets. This compound has an oral bioavailability of 30% in rats and 100% in dogs, with a half-life of 3 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 H₄ receptor plays a role in the inflammatory process. Selective H₄ receptor antagonists like JNJ 7777120 may have the potential to be useful in treating inflammation in humans.

Address correspondence to: Robin L. Thurmond, Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121. E-mail: rthurmon{at}prdus.jnj.com

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