Q4 · MEDICINE
Article
Author: Nanda, Kausik K ; Kett, Nathan R ; Manley, Peter J ; Li, Bing ; Bilodeau, Mark T ; Spencer, Robert H ; Dinsmore, Christopher J ; Wu, Zhicai ; Lynch, Joseph J ; Wolkenberg, Scott E ; Trotter, B Wesley ; Regan, Christopher P ; Stump, Gary L ; Cato, Matthew J ; White, Rebecca ; Lindsley, Craig W ; Hartman, George D ; Kane, Stefanie A ; Kiss, Laszlo ; Yeh, Suzie ; Wang, Jixin ; Nolt, M Brad
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.