Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2016-10, Vol.59 (19), p.9005-9017

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Late sodium current (late I Na) 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 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 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 anteriorior 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.