New potent azomethine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine containing a heteroarylphenyl partial structure.
The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diary limine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine (1) as a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vivo activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1, and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino] (1H-pyrrol-2-yl)methyl]phenol (8c), the 2-furanyl analogue 8d, and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.
Krause
M
M
Institut für Pharmazie, Freie Universität Berlin, Germany.
Rouleau
A
A
Stark
H
H
Luger
P
P
Garbarg
M
M
Schwartz
J C
JC
Schunack
W
W
D000818:Animals; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D006632:Histamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008761:Methylhistamines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D017442:Histamine Agonists; D007097:Imines; D008761:Methylhistamines; D011355:Prodrugs; C069357:alpha-methylhistamine; D006632:Histamine