Use of 5-hydroxy-4H-benzo[1,4]oxazin-3-ones as β2-adrenoceptor agonists

Novel β2-agonists with a 5-hydroxy-4H-benzo[1,4]oxazin-3-one moiety as head group are described. Systematic chemical variations at the phenethylamine residue of these compounds lead to the discovery of compound 6m as potent, full agonist of the β2-adrenoceptor with a high β1/β2-selectivity. Molecular modeling revealed an interaction between the carboxylic acid group of 6m and a lysine residue (K305) of the β2-receptor as putative explanation for the high observed selectivity. Further, compound 6m displayed in a guinea pig in vivo model a complete reversal of acetylcholine induced bronchoconstriction which lasted over the complete study time of 5 h.

Graphical abstractβ2-Adrenoceptor agonists with different substituents R were prepared and investigated in vitro and in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide