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 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 pA(2) 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 approximately 30% in rats and 100% in dogs, with a half-life of approximately 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.
Thurmond
Robin L
RL
Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. rthurmon@prdus.jnj.com
Desai
Pragnya J
PJ
Dunford
Paul J
PJ
Fung-Leung
Wai-Ping
WP
Hofstra
Claudia L
CL
Jiang
Wen
W
Nguyen
Steven
S
Riley
Jason P
JP
Sun
Siquan
S
Williams
Kacy N
KN
Edwards
James P
JP
Karlsson
Lars
L
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006633:Histamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism*; D000074040:Receptors, Histamine H4
D000893:Anti-Inflammatory Agents; C418607:HRH4 protein, human; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; C498828:Hrh4 protein, rat; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine