STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL AZOMETHINE PRODRUGS OF THE HISTAMINE H-3 RECEPTOR AGONIST (R)-ALPHA-METHYLHISTAMINE - FROM ALKYLARYL TO SUBSTITUTED DIARYL DERIVATIVES

This study was performed on the basis of recently developed prodrugs o f the histamine H-3-receptor agonist (R)-alpha-methylhistamine (1) to determine structure-activity relationships of azomethine prodrugs of 1 , in which the primary amine functionality is bioreversibly linked to aromatic ketones. Therefore, the pro-moiety was systematically altered from alkylaryl over benzylaryl to diaryl substitution. Those compound s that emerged to be stable enough during preparation were tested for their in vitro hydrolysis rates. Apparently bulky alkyl residues were capable of preventing previously observed intramolecular cyclization, but the obtained azomethines 12a-c were far too unstable to serve as p rodrugs. However, the benzylaryl imines 12d, e were stable compounds, but 12d decomposed tao rapidly under in vitro conditions, Distinctly g reater stability was provided by diaryl pro-moieties, even if strongly electron-withdrawing functionalities were introduced. Selected compou nds were also tested in vivo following p.o. application to mice. Parti cularly the trifluoromethyl substituted imine 12i proved Co be highly effective as stability and rate of conversion were well-balanced, so t hat brain penetration of 1 was strikingly facilitated. Thus 12i, a hig hly potent azomethine prodrug, may serve as an important pharmacologic al tool and, possibly, a therapeutic agent.