Azomethine prodrugs of (R)-alpha-methylhistamine, a highly potent and selective histamine H-3-receptor agonist

The histamine H-3 receptor is considered a potential target for novel drugs as it regulates the activity of various neurotransmitters in the periphera l and the central nervous system. Particularly H-3-receptor agonists have b een suggested to become valuable drugs for the treatment of several CNS dis orders, inflammatory and acid related diseases. Due to its strong basicity and polarity the highly potent and selective histamine H-3-receptor agonist (R)-alpha -methylhistamine hardly penetrates biological membranes and is f urthermore rapidly inactivvated in vivo. Thus, lipophilic, non-basic azomet hine prodrugs of (R)-alpha -methylhistamine have been developed to overcome its pharmacokinetic disadvantages. This bioreversible derivatization decre ased its basicity, increased its lipophilicity and reduced its metabolizati on. As a result the biological half-life was prolonged and oral absorption as well as penetration into the brain were significantly increased. By syst ematic variation of the pro-moiety we were able to optimize the pharmacokin etic properties which allow for both peripheral and central delivery of the parent amine. The azomethine prodrugs described herein display satisfactor y stability to be orally administered while being adequately labile to deli ver (R)-alpha -methylhistamine at sufficient concentrations in vivo. At pre sent, these azomethines not only serve as valuable tools for pharmacologica l studies related to the histamine H3 receptor, but also represent a promis ing approach to achieve therapeutic application of the histamine H3-recepto r agonist (R)-alpha -methylhistamine. Currently the parent compound of the prodrugs is under clinical development phase II.