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

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

Affiliations

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: scott_wolkenberg@merck.com.
  • 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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