Targeting protein kinases in central nervous system disorders.
Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood-brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges.
Chico
Laura K
LK
Center for Molecular Innovation and Drug Discovery, Northwestern University, Chicago, Illinois 60611, USA.
Van Eldik
Linda J
LJ
Watterson
D Martin
DM
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases