Designing innovative therapies for neuropathic pain: pros and cons of target-based drug discovery.
Designing innovative therapies for neuropathic pain: pros and cons of target-based drug discovery.
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设计神经性疼痛的创新疗法：基于靶标的药物发现的利弊。
DOI：
10.1111/jns.12079_3
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Inglese,J
中科院分区：
文献类型：
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作者：
Inglese,J
Among the many challenges facing academic translational research and the pharmaceutical industry, include the need for better preclinical models to validate drug targets. i Data has shown that most failures during Phase II trials are due to a lack of efficacy (50%) or noted toxicity (25%). ii, iii Targeting a specific protein’s function is generally the most effective means to approach developing a pharmacological basis to modify a disease. Establishing a therapeutic hypothesis utilizing a target-based approach ideally requires that the target is clinically validated, mechanistically and structurally elucidated, assayable, pharmacologically tractable, and functionally indistinguishable from the cellular context. The number of these validation criteria required in a program is dependent on what are considered acceptable levels of program risk proportionate to the overall strategy.(Table 1)Clearly the establishment of a dose–response relationship between the target and efficacy in humans also known as “clinical validation” is a highly desirable piece of evidence to have though often difficult to obtain. Evaluating the relevance of a specific target can be estimated in some cases by examining the relationship or direct involvement in rare inherited diseases. For example, Cystic Fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator (CFTR) protein. In one form of the disease a missense mutation (G551D) results in a dysfunctional CFTR protein that is expressed on the epithelial cell surface. Ivacaftor, a CFTR potentiator and approved drug developed by Vertex and the CF Foundation partially restores the chloride transport activity of the impaired protein resulting in clinical benefit.
