Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Caen, France.
UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS, 45 rue des Saints Pères, 75006, Paris, France; CQM - Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105, Funchal, Portugal.
Eur J Med Chem. 2020 Jun 1;195:112290. doi: 10.1016/j.ejmech.2020.112290. Epub 2020 Apr 3.
All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years. In order to prevent the cardiac side effects, a great number of in silico, in vitro and in vivo assays have been performed. The main goal of these studies is to understand the reasons of these effects, and then to give information or instructions to scientists involved in drug development to avoid the cardiac side effects. To evaluate anticipated cardiovascular effects, early evaluation of hERG toxicity has been strongly recommended for instance by the regulatory agencies such as U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Thus, following an initial screening of a collection of compounds to find hits, a great number of pharmacomodulation studies on the novel identified chemical series need to be performed including activity evaluation towards hERG. We provide in this concise review clear guidelines, based on described examples, illustrating successful optimization process to avoid hERG interactions as cases studies and to spur scientists to develop safe drugs.
在药物开发过程中，导致药物失败的最常见的不良反应之一是心律失常。这种失败主要与药物抑制人类 ether-à-go-go 相关基因（hERG）心脏钾通道的能力有关。多年来，人们一直高度关注早期识别生物活性化合物的 hERG 抑制特性。为了防止心脏副作用，已经进行了大量的计算、体外和体内测定。这些研究的主要目的是了解这些作用的原因，然后向参与药物开发的科学家提供信息或指导，以避免心脏副作用。为了评估预期的心血管作用，例如美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）等监管机构强烈建议早期评估 hERG 毒性。因此，在对化合物进行初步筛选以寻找命中物之后，需要对新确定的化学系列进行大量的药效修饰研究，包括对 hERG 的活性评估。我们在这篇简明的综述中提供了基于描述性示例的明确指导方针，说明了成功的优化过程，以避免 hERG 相互作用，作为案例研究，并激励科学家开发安全药物。
