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.

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 INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-velitricular 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 anterioior descending, LAD, occlusion in rabbits); with EC50 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.