Historically,drug discovery was chieflyan empirical enterprise,with the shift to a more hypothesisdriven approach occurring in the 20thcentury.Whereas drug discovery was originally directed towards identifying therape...Historically,drug discovery was chieflyan empirical enterprise,with the shift to a more hypothesisdriven approach occurring in the 20thcentury.Whereas drug discovery was originally directed towards identifying therapeutically useful agents prior to defining their mechanisms of action,it is now more common to develop a target-selective compound before assessing its potential clinical utility.For neurotherapeutics in particular this often yields ligands that may be useful as research tools,but worthless as therapeutics.Although the emphasis on target identification,or″targephilia″,has yielded novel pharmaceuticals,it has not facilitated the drug discovery process overall,especially for compounds to treat central nervous system(CNS)disorders.This is because the targephilic approach requires a keen understanding of the relationship between the target and organ system physiology,and the availability of in vivo and in vitro test systems that reliably predict human responses.The fact that the majority of CNS drugs have been identified empirically indicates the lack of knowledge about basic neurobiological processes and human behavior make drug discovery in this area less amenable to a target-based approach than for other types of therapeutics.Improving the success rate in CNS drug discovery requires a more pharmacometric-based strategy,with an emphasis on defining basic CNS function in intact animals and a more systematic in vivo behavior alanalysis of new chemical entities.Efforts should also be directed toward defining the sites of action of existing CNS drugs to aid in the design of secondgeneration agents and toward examining the CNS responses to drugs approved for other uses.Such a program requires a greater balance between,and integration of,pharmacometric and molecular techniques to maximize the contributions of science and serendipity in drug discovery.展开更多
文摘Historically,drug discovery was chieflyan empirical enterprise,with the shift to a more hypothesisdriven approach occurring in the 20thcentury.Whereas drug discovery was originally directed towards identifying therapeutically useful agents prior to defining their mechanisms of action,it is now more common to develop a target-selective compound before assessing its potential clinical utility.For neurotherapeutics in particular this often yields ligands that may be useful as research tools,but worthless as therapeutics.Although the emphasis on target identification,or″targephilia″,has yielded novel pharmaceuticals,it has not facilitated the drug discovery process overall,especially for compounds to treat central nervous system(CNS)disorders.This is because the targephilic approach requires a keen understanding of the relationship between the target and organ system physiology,and the availability of in vivo and in vitro test systems that reliably predict human responses.The fact that the majority of CNS drugs have been identified empirically indicates the lack of knowledge about basic neurobiological processes and human behavior make drug discovery in this area less amenable to a target-based approach than for other types of therapeutics.Improving the success rate in CNS drug discovery requires a more pharmacometric-based strategy,with an emphasis on defining basic CNS function in intact animals and a more systematic in vivo behavior alanalysis of new chemical entities.Efforts should also be directed toward defining the sites of action of existing CNS drugs to aid in the design of secondgeneration agents and toward examining the CNS responses to drugs approved for other uses.Such a program requires a greater balance between,and integration of,pharmacometric and molecular techniques to maximize the contributions of science and serendipity in drug discovery.
