17 beta-O-aminoalkyloximes of 5 beta-androstane-3 beta,14 beta-diol with digitalis-like activity: Synthesis, cardiotonic activity, structure-activityrelationships, and molecular modeling of the Na+,K+-ATPase receptor

A series of digitalis-like compounds with a 17-aminoalkoxyiminoaIkyl or -al kenyl substituent was synthesized and evaluated for inhibition of Na+,K+-AT Pase and for inotropic activity. The highest inhibition was found with comp ounds having the substituent in configuration 17 beta and the amino group a t a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the recepto r, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na+,K+-ATPase inhibitory potencies (IC50) 17-25 times high er than the standards digitoxigenin and digoxin and 3-11 times higher inotr opic potencies (EC50) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 do mains of Na+,K+-ATPase. Some interactions are the classical ones already de scribed in the literature; a new, very strong interaction of the basic grou p with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compound s were also studied in vivo in the anesthetized guinea pig for evaluating t heir inotropic effect versus the lethal dose. Compounds 9 and 12 showed a s lightly higher safety ratio than digoxin and deserve further evaluation.