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

Late sodium current (late <i>I</i>_Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na_v 1.5 channel, resulting in incomplete inactivation. Compound <b>4</b> (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late <i>I</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 <b>4</b> that is vastly improved from the first generation late <i>I</i>_Na inhibitor <b>1</b> (ranolazine). Compound <b>4</b> was 42 times more potent than <b>1</b> 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 <b>4</b> represents a new class of potent late <i>I</i>_Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients