Selective Kv1.5 Blockers: Development of (R)-1-(Methylsulfonylamino)-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone (KVI-020/WYE-160020) as a Potential Treatment for Atrial Arrhythmia

Abstract

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Current treatments extend the atrial effective refractory period by nonselective blockade of cardiac ion channels. An alternative approach selectively targeting the Kv1.5 ion channel offers the opportunity for therapeutic benefit with decreased risk of adverse cardiovascular events. KVI-020 (4g) successfully demonstrated antiarrhythmic efficacy in a canine arrhythmia model, and these findings support its utility as an antiarrhythmic agent.

Rotor Termination Is Critically Dependent on Kinetic Properties of IKur Inhibitors in an In Silico Model of Chronic Atrial Fibrillation

“…Olson and co-workers reported a loss-of-function mutation within the Kv1.5 potassium channel, the molecular basis of human I Kur , as the cause of a form of familial AF [7]. Furthermore, pharmacological inhibition of I Kur has been associated with both anti- and pro-arrhythmic effects on human atrial cells [6], [8]–[13]. These obvious inconsistencies might be explained by individual kinetic properties of the different I Kur inhibitors, including time- and voltage-dependence of block as well as simultaneous inhibitory effects on other cardiac ion channels [14].…”

Acyclic and Cyclic Ureas (Update 2013)

“…[330,331] Standard nitrosation conditions are much milder and can often be used to install a nitroso group onto a urea NH moiety. Reagents that can be used include nitrous acid, [332] tert-butyl nitrate, [333] or nitrosyl tetrafluoroborate. [334] 3,4-Dihydropyrimidin-2(1H)-ones, the products of the Biginelli reaction (see Section 18.8.22.3.1.2), can be nitrosated regioselectively at the N3 position by bubbling purified nitric oxide through a solution of the starting material in acetonitrile at room temperature in the presence of trace amounts of oxygen.…”

Synthesis of a Small Library of Imidazolidin-2-ones using Gold Catalysis on Solid Phase

“…[27][28][29][30] As part of our research program concerning the application of organometallic chemistry to the solid-phase synthesis, [31][32][33][34] herein we report the synthesis of a small library of imidazolidin-2-ones using gold catalysis on propargylureas bonded to solid support. Imidazolidin-2-ones possess a variety of biological activities, including antileishmanil activity, 35 MurB enzyme inhibitors possessing antibacterial activity, 36 antiviral activity, 37 antiarrhythmic, 38 selective high-affinity antagonists for the human dopamine D4 receptor, 39 and anticancer agents. 40,41,42 There are several studies on the cycloisomerization of alkynylureas in solution phase, some of them involving the synthesis of bicyclic heterocycles starting from (ortho-arylalkynyl)ureas 43,44 and others describing the formation of monocyclic heterocycles from in situ generated propargylureas.…”