Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I Na i), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

作者：Jeff Zablocki, Elfatih Elzein, Xiaofen Li, Dmitry O. Koltun, Eric Q. Parkhill, Tetsuya Kobayashi, Ruben Martinez, Britton K. Corkey, Haibo Jiang, Thao Perry, Rao Kalla, Gregory T. Notte, Oliver L. Saunders, Michael Graupe, Yafan Lu, Chandru Venkataramani, Juan Guerrero, Jason K. Perry, Mark R Osier, Robert G. Strickley, Gongxin Liu, Weiqun Wang, Lufei Hu, Xiaojun Li, Nesrine El‐Bizri, Ryoko Hirakawa, Kris Kahlig, Cheng Xie, Cindy Hong Li, Arvinder K. Dhalla, Sridharan Rajamani, Névéna Mollova, Daniel Soohoo, Eve‐Irene Lepist, Bernard P. Murray, Gerry Rhodes, Luiz Belardinelli, Manoj C. Desai · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b00939 · 被引用次数：35 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Receptor Mechanisms and Signaling

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia–ventricular fibrillation (VT–VF). We will describe structure–activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S–T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.