Erdemli Gül, Kim Albert M, Ju Haisong, Springer Clayton, Penland Robert C, Hoffmann Peter K
Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research Cambridge, MA, USA.
Front Pharmacol. 2012 Jan 26;3:6. doi: 10.3389/fphar.2012.00006. eCollection 2012.
The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.
人类心脏钠通道（由SCN5A基因编码的hNav1.5）对于心脏中动作电位的产生和传导至关重要。药物诱导的钠通道抑制会降低心肌细胞的去极化速率，进而降低传导速度，并且可能对心脏安全性产生严重影响。hNav1.5中的基因突变也与多种心脏疾病有关。因此，脱靶的hNav1.5抑制可能被视为候选药物的一个风险指标。鉴于对患者的潜在安全影响以及后期药物开发、检测和缓解的成本，在药物发现和开发的早期阶段检测和减轻hNav1.5的不良反应就变得很重要。在这篇综述中，我们描述了一种临床前策略，用于识别hNav1.5的不良反应，该策略结合了体外、体内和计算机模拟技术，以及这些信息在药物发现和开发不同阶段的综合风险评估中的应用。
