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

2008; American Chemical Society; Volume: 51; Issue: 15 Linguagem: Inglês

10.1021/jm800257s

1520-4804

Mauro Gobbini, Silvia Armaroli, Leonardo Banfi, Alessandra Benicchio, Giulio Carzana, Giorgio Fedrizzi, Paolo Ferrari, Giuseppe Giacalone, Michele Giubileo, Giuseppe Marazzi, R. Micheletti, Barbara Moro, Marco Pozzi, Piero Enrico Scotti, Marco Torri, Alberto Cerri,

Enzyme function and inhibition

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 5α,14α-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 5α,14α-androstane.