The discovery of first-in-class drugs: origins and evolution
The discovery of first-in-class drugs: origins and evolution
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DOI：
10.1038/nrd4336
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发表时间：
2014-08-01
影响因子：
120.1
通讯作者：
Wiesmann, Christian
中科院分区：
文献类型：
--
作者：
Eder, Joerg;Sedrani, Richard;Wiesmann, Christian
对1999年至2008年美国食品和药物管理局(FDA)批准的新药来源的分析表明，在发现一流小分子药物方面，表型筛选策略比基于目标的方法更有成效。然而，考虑到在药物开发的较长时间框架内采用以目标为基础的办法相对较近，其全面影响可能尚未显现。在这里，我们对1999年至2013年FDA批准的所有113种一类药物的来源进行了分析，结果表明，大多数(78种)是通过靶向方法发现的(45种小分子药物和33种生物制品)。此外，在33种在没有靶点假说的情况下确定的药物中，有25种是通过化学中心法发现的，其中以已知药理的化合物为起点，只有8种药物来自我们在这里定义的表型筛选：在监测表型变化的靶标不可知试验中测试大量化合物。我们还讨论了药物发现策略的含义，包括将表型筛选视为一种新的学科，而不是一种新古典方法。
Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.