Novel Analogues of Istaroxime, a Potent Inhibitor of Na⁺,K⁺-ATPase: Synthesis and Structure−Activity Relationship

Abstract

We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.

Novel analogues of Istaroxime, a potent inhibitor of Na+,K+-ATPase: Synthesis, structure–activity relationship and 3D-quantitative structure–activity relationship of derivatives at position 6 on the androstane scaffold

“…5,8 This assertion is supported by comparison of the few available experimental inhibitory data of the correlated E/Z mixture, the pure E and the Z isomers. In the following examples, both the inhibition value of the E isomer and the one of the mixture are always higher than the value of the Z isomer: 5 its E isomer (2.0 lM) 4 and its Z isomer (12.0 lM).…”

“…The choice of the three different amines was based on their potencies and different structures, as reported in a recent study about the systematic variation of the oximic chain present in Istaroxime. 8 The 2-aminoethyl oxime was chosen as reference chain since it is present in Istaroxime and as example of primary amine with high potency. The (3R)-3-pyrrolidinyloxyimino chain was used because some cyclic amines on the oximic group at position 3 gave compounds with a higher inhibitory potency than the linear amine analogues (in particular (E,Z)-3-[(3R)-3-pyrrolidinyloxyimino]androstane-6,17-dione, compound C, was found to be about four times more potent than Istaroxime) and as example of a secondary cyclic amine.…”

“…The same feature is present also in 3, but the extra methyl group on the double bond is oriented in the opposite direction with respect to the proposed nonpolar favorable region; this fact could explain its 25-fold reduced activity compared to that of 1. The other two compounds carry a double (7) or a triple (8) bond roughly on the same plane that contains the androstane scaffold; as the more straight alkynyl group gave a higher inhibitory activity, we can suppose that this zone of the receptor is very selective in respect to the position of the substituent; again, as for 1, the molecule could rotate on the major axis of the androstane's plane, thus permitting the alkynyl group to reach the nonpolar zone occupied by the D ring of digitoxigenin.…”

“…6,7 In the previous paper, the androstane skeleton was used as a scaffold to study the space around the basic chain in position 3 of our lead compound, Istaroxime; some compounds demonstrated higher potencies than Istaroxime on the receptor and all tested compounds resulted less proarrhythmogenic than digoxin. 8 In this paper, we describe new analogues of Istaroxime in which the effects of substitution at position 6 of the androstane scaffold on the activity at the Na + ,K + -ATPase were studied. We performed a wide differentiation of the carbonyl group present at position 6 of Istaroxime, with the purpose of obtaining compounds with a higher potency and better therapeutic index than those of the parent compound.…”

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

“…Searching for these molecules has yielded istaroxime analogs with better activity, and even structure-activity relationships have been found. 45,46 Further, a high-throughput fluorescence resonance energy transfer assay has been used to find allosteric SERCA2a activators capable of decreasing SERCA2a/PLN-derived fluorescence resonance energy transfer. 47 In this study, several compounds previously reported to correct aberrant Ca 2+ regulation in HF were shown to activate SERCA2a activity, thus validating the mechanism of action for these drugs.…”