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New Potent Azomethine Prodrugs of the Histamine H 3 ‐Receptor Agonist ( R )‐α‐Methylhistamine Containing a Heteroarylphenyl Partial Structure
Author(s) -
Krause Michael,
Rouleau Agnès,
Stark Holger,
Luger Peter,
Garbarg Monique,
Schwartz JeanCharles,
Schunack Walter
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290407
Subject(s) - chemistry , agonist , prodrug , histamine , partial agonist , histamine h3 receptor , stereochemistry , chemical synthesis , pharmacology , receptor , biochemistry , in vitro , medicine
The therapeutic value of histamine H 3 ‐receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H 3 ‐receptor agonist ( R )‐α‐methyl‐histamine ( 1 ) a series of new azomethine prodrugs containing five‐ and six‐membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro 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‐(1 H ‐imidazol‐4‐yl)‐2‐propyl]imino](1 H ‐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 H 3 ‐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.