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ID: ALA4715705
Journal: ACS Med Chem Lett
Title: Aminotriazole and Aminotetrazole Inhibitors of LSD1 as Epigenetic Modulators.
Authors: Kumar V,Rosse G
Abstract: Late sodium current (late I) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I, 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 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 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.
CiteXplore: 26985286