6 research outputs found
Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late <i>I</i><sub>Na</sub>i), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties
Late
sodium current (late <i>I</i><sub>Na</sub>) is enhanced
during ischemia by reactive oxygen species (ROS) modifying the Na<sub>v</sub> 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><sub>Na</sub>, is currently in clinical
development for treatment of long QT-3 syndrome (LQT-3), hypertrophic
cardiomyopathy (HCM), and ventricular tachycardiaâventricular
fibrillation (VTâVF). We will describe structureâactivity
relationship (SAR) leading to the discovery of <b>4</b> that
is vastly improved from the first generation late <i>I</i><sub>Na</sub> inhibitor <b>1</b> (ranolazine). Compound <b>4</b> was 42 times more potent than <b>1</b> in reducing
ischemic burden in vivo (SâT segment elevation, 15 min left
anteriorior descending, LAD, occlusion in rabbits) with EC<sub>50</sub> values of 190 and 8000 nM, respectively. Compound <b>4</b> represents a new class of potent late <i>I</i><sub>Na</sub> inhibitors that will be useful in delineating the role of inhibitors
of this current in the treatment of patients