Azomethine prodrugs of (R)-alpha-methylhistamine, a highly potent and selective histamine H3-receptor agonist

The histamine H3 receptor is considered a potential target for novel drugs as it regulates the activity of various neurotransmitters in the peripheral and the central nervous system. Particularly H3-receptor agonists have been suggested to become valuable drugs for the treatment of several CNS disorders, inflammatory and acid related diseases. Due to its strong basicity and polarity the highly potent and selective histamine H3-receptor agonist (R)-alpha-methylhistamine hardly penetrates biological membranes and is furthermore rapidly inactivated in vivo. Thus, lipophilic, non-basic azomethine prodrugs of (R)-alpha--methylhistamine have been developed to overcome its pharmacokinetic disadvantages. This bioreversible derivatization decreased its basicity, increased its lipophilicity and reduced its metabolization. As a result the biological half-life was prolonged and oral absorption as well as penetration into the brain were significantly increased. By systematic variation of the pro-moiety we were able to optimize the pharmacokinetic properties which allow for both peripheral and central delivery of the parent amine. The azomethine prodrugs described herein display satisfactory stability to be orally administered while being adequately labile to deliver (R)-alpha-methylhistamine at sufficient concentrations in vivo. At present, these azomethines not only serve as valuable tools for pharmacological studies related to the histamine H3 receptor, but also represent a promising approach to achieve therapeutic application of the histamine H3-receptor agonist (R)-alpha-methylhistamine. Currently the parent compound of the prodrugs is under clinical development phase II.