There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alt...There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.展开更多
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There are two general approaches to drug discovery. The oldest is the empirically-driven in vivo identification of a drug candidate, with little or no consideration given to identifying the active constituent. The alternative is mechanism-based, a process that entails the in vitro screening of purified chemical compounds to identify those that interact specifically with a selected biological target, after which they are tested for therapeutic potential. A major difference between these approaches is the extent to which the principles of pharmacology are employed to demonstrate safety and efficacy and to enable improvements in the therapeutic properties of the product. As a thorough pharmacological analysis of the pharmacokinetics and pharmacodynamics of a test agent requires that it be a stable, single, purified substance, such testing is more difficult with unpurified samples containing multiple compounds as compared to single agents. A lack of pharmacological information compromises the clinical utility of a test substance by leaving open questions about its bioavailability, metabolism, and mechanisms of therapeutic actions and toxicities. Although drug discovery success has be achieved with both the empirically-driven and mechanism-based approaches, the proper application of pharmacological techniques in the drug discovery process maximizes efficacy, safety and the chance for regulatory approval. In addition, pharmacological data provides information needed for improving the therapeutic properties of an agent, enhancing its clinical utility, and extending the product lifespan.
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.
