Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

Bioorganic & medicinal chemistry letters 2017 Feb 15

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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. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Scott E Wolkenberg, M Brad Nolt, Mark T Bilodeau, B Wesley Trotter, Peter J Manley, Nathan R Kett, Kausik K Nanda, Zhicai Wu, Matthew J Cato, Stefanie A Kane, Laszlo Kiss, Robert H Spencer, Jixin Wang, Joseph J Lynch, Christopher P Regan, Gary L Stump, Bing Li, Rebecca White, Suzie Yeh, Christopher J Dinsmore, Craig W Lindsley, George D Hartman. Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics. Bioorganic & medicinal chemistry letters. 2017 Feb 15;27(4):1062-1069