ABSTRACT
Among the cardiotonics (agents against congestive heart failure), the most important group is of the digitalis cardiac glycosides, but since these compounds suffer from a low therapeutic index, attention has been paid to investigating safer cardiotonic agents through the inhibition of Na+,K(+)-ATPase, the mechanism by which the digitalis cardiac glycosides elicit their action. Recently, a series of perhydroindenes were studied for their Na+,K(+)-ATPase inhibition activity. We report here a QSAR study on them to investigate the physicochemical and structural properties of the molecules that govern their activity in order to rationalize the structural modification to have more potent drugs. A multiple regression analysis reveals a significant correlation between the Na+,K(+)-ATPase inhibition activity of the compounds and Kier's first order valence molecular connectivity index of their R5-substituents and some indicator parameters, suggesting that the R5-substituents of the compounds containing atoms with low valence and high saturation and the R1-substituents having =N-O- moiety will be conducive to the activity.
Subject(s)
Cardiotonic Agents/chemistry , Cardiotonic Agents/chemical synthesis , Digitalis/chemistry , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Digitalis Glycosides/antagonists & inhibitors , Digitalis Glycosides/chemistry , Enzyme Inhibitors/chemistry , Quantitative Structure-Activity Relationship , Regression AnalysisABSTRACT
There has been an increasing interest in compounds that modulate potassium ion channels (K(+)-channels) since they can be developed as important therapeutic agents against ischemic heart diseases. Of the diverse family of K(+)-channels, the voltage-gated potassium channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T cells in autoimmune diseases. For the development of antiarrythmic drugs, the blockade of the rapidly activating delayed rectifier (I(Kr)) and slowly activating delayed rectifier (I(Ks)) potassium currents has been specifically studied. Since the discovery of I(Ks)-channel, its blockers have been particularly more studied. In this communication, we present QSAR studies on a few series of Kv1.3-channel blockers and a series of I(Ks)-channel blockers in order to provide some guidelines to the drug development.
