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

  • Bioorg Med Chem Lett. 2017 Feb 15;27(4):1062-1069. doi: 10.1016/j.bmcl.2016.12.054.
Scott E Wolkenberg  1 ,  M Brad Nolt  2 ,  Mark T Bilodeau  2 ,  B Wesley Trotter  2 ,  Peter J Manley  2 ,  Nathan R Kett  2 ,  Kausik K Nanda  2 ,  Zhicai Wu  2 ,  Matthew J Cato  3 ,  Stefanie A Kane  3 ,  Laszlo Kiss  3 ,  Robert H Spencer  3 ,  Jixin Wang  3 ,  Joseph J Lynch  4 ,  Christopher P Regan  4 ,  Gary L Stump  4 ,  Bing Li  5 ,  Rebecca White  5 ,  Suzie Yeh  5 ,  Christopher J Dinsmore  2 ,  Craig W Lindsley  2 ,  George D Hartman  2
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: [email protected].
  • 2. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 3. Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 4. Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
  • 5. Department of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
PMID: 28131713 DOI: 10.1016/j.bmcl.2016.12.054
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.

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