Challenges and Opportunities in Central Nervous System Drug Discovery

Disorders of the central nervous system (CNS) are responsible for multiple disease states of significant economic and social impact. The role that medicinal chemistry can have in alleviating these impacts is substantial, but key factors and challenges exist for CNS drug discovery that are not often encountered for other disease targets. Hit identification has developed to incorporate target-based screening, multitarget-directed ligands, and phenotypic screening all as a means to combat the poor translation from lab to clinic. Recent advances in microfluidics have sought to improve this translation rate by developing organ-on-a-chip technologies. Developing chemistry has also played an important role in improving CNS drug discovery. Late-stage functionalization, fluorine or deuterium incorporation, and the use of polycycles are some techniques chemists have been able to employ in the drug discovery process. The development of new drugs for disorders of the central nervous system (CNS) presents unique challenges when compared with other disease areas. These include an incomplete understanding of the biology of multifaceted CNS conditions such as Alzheimer’s disease, the presence of a blood–brain barrier that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models in which to test new drugs. In this review, we aim to discuss some of these issues at each stage of the drug discovery process, provide examples of recent work addressing them, and consider the options available to researchers in the future. The development of new drugs for disorders of the central nervous system (CNS) presents unique challenges when compared with other disease areas. These include an incomplete understanding of the biology of multifaceted CNS conditions such as Alzheimer’s disease, the presence of a blood–brain barrier that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models in which to test new drugs. In this review, we aim to discuss some of these issues at each stage of the drug discovery process, provide examples of recent work addressing them, and consider the options available to researchers in the future. when misfolded proteins clump together to form large, generally insoluble, masses and are correlated with a number of disease states. a dynamic and selective protective membrane that restricts the flow of native and foreign agents between the blood and CNS. simulates the activities, mechanics, and physiological response of an organ or series of organs. these arise from a combination of genetic, lifestyle, and environmental factors rather than a single mutation. Treatment of these disease types often requires multiple treatment types or treatments that focus on more than target. the progressive loss of neuron function or structure leading to a number of neurological disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis. the inflammation response in the CNS to various cues, such as infection or traumatic brain injury, from the resident immune cells (microglia). Chronic inflammation leads to neurodegenerative diseases. these are used to determine permeability of a compound and are designed to mimic various membranes, such as the BBB. a method of identifying molecules of interest in a drug discovery program. The desired response is examined in a whole cell or organism rather than the response at a particular target. a method of providing 3D images of internal bodily functions by using positron-emitting radionuclei such as 18F, 11C, or 124I attached to a biologically active molecule.