From Magic Bullet To Magic Pump Gun: Multi-targeting Drugs For Neurodegenerative Diseases
Neurodegenerative diseases are characterized by complex and multifactorial mechanisms, which are not completely understood. In particular, the molecular causes of many neurodegenerative diseases have not been identified, but numerous factors contributing to progress of disease. Alzheimer’s or Parkinson’s disease are the two most important representatives with high medical need for new medical entities. Despite identification of numerous biochemical targets for potential drug therapy of neurodegenerative diseases, sufficient medicinal therapies are still missing.
Instead of having one target to be addressed, there are numerous targets that need to be influenced in absence of the knowledge on the exact cause. Innovative “multitargeting” strategies were developed to fight the various biochemical mechanisms involved in neurodegeneration. Compared to the former one-drug-one-target approach based on Paul Ehrlich’s magic bullet, multitargeting drugs regulate more than one target at once demonstrating selected promiscuity. Thus, multitargeting drugs may modulate different, but connected biochemical targets more efficiently. In addition to the pharmacodynamics interactions, one may prefer application of a multitargeting drug rather than a cocktail of one-target-directed drugs, which may cause numerous pharmacokinetic problems due to different drug timings, half-lives, metabolism etc. The one drug-approach improves handling for patients and simplifies the drug development process e.g. by reducing potential drug-drug interactions.
The development of antioxidants represents an established strategy for treatment of neurodegenerative disease, in particular Alzheimer’s disease, since inflammatory processes and oxidative stress are possible reasons for neuronal cell death. Recently, a new, complex and elegant approach on these multiple targeting has been described with its design as well as synthesis for biologically active anti-oxidative compounds addressing simultaneously different neurotransmitter-catabolizing enzymes (i.e., acetyl‑/ butyrylcholinesterases and monoamine oxidases A/B) as well as the transmembrane G-protein coupled histamine H3 receptor (H3R) in low concentrations. All five molecular targets are identified as key player in neurodegeneration and/or on regulation of critical neurotransmitter levels. The small series of multitarget-directed ligands was optimized by knowledge-based introduction of various H3R structural elements based on previously described anti-oxidant lead structures.
The balanced in vitro profile was successfully extended by wanted and reduced by unwanted effects to obtain an optimized pharmacological profile for neurodegenerative diseases. The most promising candidate Contilisant showed the required capability of penetrating the blood-brain barrier combined with anti-oxidative and neuroprotective capacities (e.g. on beta-amyloid plagues). In vivo, Contilisant was able to significantly restore cognitive deficits in impaired mice at low dosage.
This unique pharmacological profile of Contilisant demonstrates the knowledge-based actual capabilities in drug design. The translation of disease mechanism into a complex drug design as presented bears the chance for more comprehensive treatment of neurodegenerative diseases, such as Alzheimer´s or Parkinson´s disease. The multitargeting approach is a hot topic in drug design and handled in an EU funded Cooperation of Science and Technology “Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig, COST CA15135)” led by Stefano Alcaro, Italy.
This study, Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases, was recently published as hot paper by Stefanie Hagenow, Holger Stark and co-workers in the journal Angewandte Chemie – International Edition.