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 During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H 4 but not H 3 receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2 Histamine (0.01-30 mM) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 mM histamine with EC 50 at 19 nM. After 60 min incubation with 1 mM histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 mM) also enhanced the eosinophil shape change induced by other chemokines. 3 Histamine-induced eosinophil shape change was mediated by the H 4 receptor. This effect was completely inhibited by H 4 receptor-specific antagonist JNJ 7777120 (IC 50 0.3 mM) and H 3 /H 4 receptor antagonist thioperamide (IC 50 1.4 mM), but not by selective H 1 , H 2 or H 3 receptor antagonists. H 4 receptor agonists imetit (EC 50 25 nM) and clobenpropit (EC 50 72 nM) could mimic histamine effect in inducing eosinophil shape change. 4 Histamine (0.01-100 mM) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. This effect was mediated by the H 4 receptor and could be blocked by H 4 receptor antagonists JNJ 7777120 and thioperamide. 5 Histamine (0.01-10 mM) induced eosinophil chemotaxis with an EC 50 of 83 nM. This effect was mediated by the H 4 receptor and could be blocked by H 4 receptor antagonists JNJ 7777120 (IC 50 86 nM) and thioperamide (IC 50 519 nM). Histamine (0.5 mM) also enhanced the eosinophil shape change induced by other chemokines. 6In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H 4 receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H 4 receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H 4 receptor antagonists.

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.

Studies toward the development of an enantioselective diazomethane-based cyclopropanation reagent derived from bis(oxazoline)palladium(II) complexes are reported. Several simple palladium chelates, 2 and 7, in addition to the novel carbon-bound complexes 15 were synthesized and evaluated in the cyclopropanation of various electron-deficient olefins. The X-ray crystal structure of aryl−bis(oxazoline)palladium complex 15c is described. Although all catalysts efficiently affected cyclopropanation, all products were racemic. An intriguing relationship between substitution on the oxazoline ring, particularly the commonly-derivatized 4-position, and catalyst efficiency was discovered. The results are rationalized by either partial or complete bis(oxazoline) decomplexation during the course of the reaction.

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