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

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

doi:10.1016/j.bmcl.2016.12.054

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. Epub 2017 Jan 16.

Authors

Scott E Wolkenberg¹, M Brad Nolt², Mark T Bilodeau², B Wesley Trotter², Peter J Manley², Nathan R Kett², Kausik K Nanda², Zhicai Wu², Matthew J Cato³, Stefanie A Kane³, Laszlo Kiss³, Robert H Spencer³, Jixin Wang³, Joseph J Lynch⁴, Christopher P Regan⁴, Gary L Stump⁴, Bing Li⁵, Rebecca White⁵, Suzie Yeh⁵, Christopher J Dinsmore², Craig W Lindsley², George D Hartman²

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, I_Kur, 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 I_Ks, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for I_Kur over I_Ks (>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.

MeSH terms

Drug Discovery
Humans
Kv1.5 Potassium Channel / antagonists & inhibitors*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

KCNA5 protein, human
Kv1.5 Potassium Channel
MK-1832
Pyridines