title: Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.
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 IKurover 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: scott_wolkenberg@merck.com.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Wolkenberg
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: M Brad
authors.initials: MB
authors.lastname: Nolt
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Kett
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cato
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kiss
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Spencer
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Jixin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Stump
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: White
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Suzie
authors.initials: S
authors.lastname: Yeh
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D055808:Drug Discovery; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; C000621944:MK-1832; D011725:Pyridines