Discovery of multitargeting chemical entities for the treatment of Parkinson's disease

Since half of the world's older population lives in Asia, neurodegenerative diseases including Parkinson‘s disease (PD) become a serious problem that should be investigated in greater depth in this region. Indeed, there is a huge effort towards the identification of new, effective and safe drugs for the successful therapy of PD: previous approaches focused on highly selective compounds targeting individual proteins (i.e., ―one compound-one target‖ approach). Subsequently, poly-pharmacology has gained much interest, since the heterodimerization of A2A adenosine receptors and D2 dopamine receptors in the brain was established. Hence, recent anti-parkinson therapies combine A2A antagonists and D2 selective agonists through a ―cocktail drugs-multiple targets‖ approach. Although a few multi-component therapies have entered clinical trials, these methodologies are often associated with side effects, due to the complicated interaction among drugs and different pharmacokinetic profiles. In view of these limitations, we have brought together key leaders with diversified expertise, in order to identify New Chemical Entities that are able to modulate the activity of both D2 and A2A receptors simultaneously (i.e., ―one compound-multiple targets‖ approach). The advantages associated with this strategy encompass avoidance of drug-drug interactions, clear pharmacokinetic and pharmacodynamic profiles, more predictable metabolic instabilities and more likely lower side effects. Indeed, none of the proposed treatments for PD uses a single molecule to trigger the desired therapeutic effects. This project includes molecular modeling, organic syntheses, crystallography, genetic studies as well as in vitro and in vivo pharmacological evaluations, through a multi-institutional initiative involving the National University of Singapore, the Nanyang Technological University, the Duke-NUS Medical School, the Drug Development Unit and a few European academic partners. This team effort will result not only in the development of more effective drug candidates or better models of disease, but it will enable the translation of these new methodologies into clinically relevant medicine paradigms.