MEDI 449 |
| The development of ion channel blockers for the treatment of atrial fibrillation (AF) has attracted widespread interest in recent years. The prevalence of AF is rising as the population ages, and the disease has been identified as a major contributor to stroke and resultant morbidities and mortalities. Because current therapies can promote potentially lethal ventricular proarrhythmia, we have focused on antagonists of the Kv1.5 potassium channel and its associated current, IKur, which is observed in the human atrium but not in ventricle. We present here the synthesis and optimization of Kv1.5 antagonists guided by ion channel assay data, pharmacokinetic evaluation, and in vivo rat and dog cardiac electrophysiological experiments. Studies of key compounds have led to the identification of orally bioavailable antagonists that selectively increase atrial refractory period in a dog pharmacodynamic model. |
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Antiarrhythmic Agents
9:00 AM-12:00 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |