In vitroandin vivocharacterization of A‐940894: a potent histamine H4receptor antagonist with anti‐inflammatory properties

Open Access
Publisher Website
Google Scholar
Abstract
Background and purpose: The histamine H4receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe thein vitroandin vivoanti‐inflammatory properties of a potent histamine H4receptor antagonist, A‐940894 (4‐piperazin‐1‐yl‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidin‐2‐ylamine).Experimental approach: We have analysed the pharmacological profile of A‐940894 at mouse native, rat recombinant and human recombinant and native, histamine H4receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan‐induced peritonitis.Key results: A‐940894 potently binds to both human and rat histamine H4receptors and exhibits considerably lower affinity for the human histamine H1, H2or H3receptors. It potently blocked histamine‐evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine‐induced shape change of mouse bone marrow‐derived mast cells and chemotaxis of human eosinophilsin vitro. In a mouse mast cell‐dependent model of zymosan‐induced peritonitis, A‐940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2levels. Finally, A‐940894 has good pharmacokinetic properties, including half‐life and oral bioavailability in rats and mice.Conclusions and Implications: These data suggest that A‐940894 is a potent and selective histamine H4receptor antagonist with pharmacokinetic properties suitable for long‐termin vivotesting and could serve as a useful tool for the further characterization of histamine H4receptor pharmacology.

This publication has 35 references indexed in Scilit: