title: The emergence of designed multiple ligands for neurodegenerative disorders.
abstract: The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline.
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University (NEOMED), 4209 State Route 44, Rootstown, OH 44272, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Richard T
authors.initials: RT
authors.lastname: Carroll
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000978:Antiparkinson Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D000978:Antiparkinson Agents; D008024:Ligands; D018696:Neuroprotective Agents