Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds.

The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses.

Synthesis and inotropic activity of 1-(O-aminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na(+),K(+)-ATPase.

A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-ol derivatives bearing a 1(S)-(omega-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-Parrish ketol 47, as simplified analogues of very potent 17beta-aminoalkyloximes with digitalis skeleton, previously reported. The target compounds were evaluated in vitro for displacement of the specific [3H]ouabain binding from the dog kidney Na(+),K(+)-ATPase receptor. Some of them revealed IC(50) values in the micromolar range. The most active compounds possess a cyclohexyl group in the 5(S) position and in position 1(S) the same aminoalkyloxime groups already reported for the digitoxigenin-like series in position 17beta. Although the ring conformation of these derivatives was comparable to that of uzarigenin, the binding affinities of the most active ones were 4/8-fold lower in comparison to that standard. Three compounds among those with the highest affinities were assayed in vitro for their inotropic activity on an electrically driven guinea pig left atrium and were found to be less potent than both digoxin, the most widely used inotropic agent, and the corresponding digitalis 17beta-aminoalkyloximes.