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


Journal of Medicinal Chemistry


Jeff A. Zablocki*†, Elfatih Elzein†, Xiaofen Li†, Dmitry O. Koltun†, Eric Q. Parkhill†, Tetsuya Kobayashi†, Ruben Martinez†, Britton Corkey†, Haibo Jiang†, Thao Perry†, Rao Kalla†, Gregory T. Notte†, Oliver Saunders†, Michael Graupe†, Yafan Lu†, Chandru Venkataramani†, Juan Guerrero†, Jason Perry⊥, Mark Osier§, Robert Strickley∥,Gongxin Liu#, Wei-Qun Wang#, Lufei Hu#, Xiao-Jun Li#, Nesrine El-Bizri#, Ryoko Hirakawa#, Kris Kahlig#, Cheng Xie#, Cindy Hong Li#, Arvinder K. Dhalla#, Sridharan Rajamani#, Nevena Mollova‡, Daniel Soohoo‡, Eve-Irene Lepist‡, Bernard Murray‡, Gerry Rhodes‡, Luiz Belardinelli#, and Manoj C. Desai†



Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, 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 INa 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 EC50 values of 190 and 8000 nM, respectively. Compound 4represents a new class of potent late INa inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

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