Center for Proteomic Chemistry, Novartis Pharma AG, Forum 1, 4002 Basel, Switzerland.
Future Med Chem. 2009 Jul;1(4):645-65. doi: 10.4155/fmc.09.51.
One of the main reasons for drug failures in clinical development, or postmarket launch, is lacking or compromised safety margins at therapeutic doses. Organ toxicity with poorly defined mechanisms and adverse drug reactions associated with on- and off-target effects are the major contributors to safety-related shortfalls of many clinical drug candidates. Therefore, to avoid high attrition rates in clinical trials, it is imperative to test compounds for potential adverse reactions during early drug discovery. Beyond a small number of targets associated with clinically acknowledged adverse drug reactions, there is little consensus on other targets that are important to consider at an early stage for in vitro safety pharmacology assessment. We consider here a limited number of safety-related targets, from different target families, which were selected as part of in vitro safety pharmacology profiling panels integrated in the drug-development process at Novartis. The best way to assess these targets, using a biochemical or a functional readout, is discussed. In particular, the importance of using cell-based profiling assays for the characterization of an agonist action at some GPCRs is highlighted. A careful design of in vitro safety pharmacology profiling panels allows better prediction of potential adverse effects of new chemical entities early in the drug-discovery process. This contributes to the selection of the best candidate for clinical development and, ultimately, should contribute to a decreased attrition rate.
药物在临床开发或上市后失败的主要原因之一是治疗剂量下缺乏或安全边际受损。机制不明确的器官毒性和与靶内和靶外效应相关的药物不良反应是许多临床候选药物安全性不足的主要原因。因此，为了避免临床试验中的高淘汰率，在药物发现的早期阶段测试化合物的潜在不良反应至关重要。除了与临床公认的药物不良反应相关的少数靶点外，对于在体外安全药理学评估的早期阶段需要考虑的其他靶点，几乎没有共识。我们在这里考虑了一些数量有限的与安全性相关的靶点，这些靶点来自不同的靶家族，它们被选为诺华药物开发过程中整合的体外安全药理学特征分析面板的一部分。讨论了使用生化或功能读数来评估这些靶标的最佳方法。特别是，强调了使用基于细胞的分析测定法来表征某些 GPCR 激动剂作用的重要性。精心设计的体外安全药理学特征分析面板可以更好地预测新化学实体在药物发现过程早期的潜在不良反应。这有助于选择最佳的临床开发候选药物，最终应该有助于降低淘汰率。
