Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides

Kausik K Nanda; M Brad Nolt; 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; Michael J Bogusky; Mark T Bilodeau; Christopher J Dinsmore; Craig W Lindsley; George D Hartman; Scott E Wolkenberg; B Wesley Trotter

doi:10.1016/j.bmcl.2006.08.054

Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides

Bioorg Med Chem Lett. 2006 Nov 15;16(22):5897-901. doi: 10.1016/j.bmcl.2006.08.054. Epub 2006 Sep 1.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., PO Box 4, West Point, PA 19486, USA.

PMID: 16949818
DOI: 10.1016/j.bmcl.2006.08.054

Abstract

This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed. Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model.

Publication types

Evaluation Study

MeSH terms

Acetamides / chemical synthesis*
Acetamides / pharmacology*
Animals
Dogs
Kv1.5 Potassium Channel / antagonists & inhibitors*
Potassium Channel Blockers / chemical synthesis*
Potassium Channel Blockers / pharmacology*
Pyridines / chemical synthesis*
Pyridines / pharmacology*
Stereoisomerism
Structure-Activity Relationship
Time Factors
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / pharmacology

Substances

1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea
Acetamides
Kv1.5 Potassium Channel
Potassium Channel Blockers
Pyridines
Urea