| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA;2. Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA;3. Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA;4. Department of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA |
| Abstract: | Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans. |
