17α-O-(Aminoalkyl)oxime Derivatives of 3β,14β-Dihydroxy-5β-androstane and 3β-Hydroxy-14-oxoseco-D-5β-androstane as Inhibitors of Na+,K+-ATPase at the Digitalis Receptor

Abstract

The synthesis and binding affinities to the digitalis Na⁺,K⁺-ATPase receptor of a series of 3β,14β-dihydroxy-5β-androstane and 3β-hydroxy-14-oxoseco-D-5β-androstane derivatives bearing a 17α-(aminoalkoxy)imino chain are reported; some derivatives were also studied for their inotropic activity. Our recently proposed model of interaction of molecules with the digitalis receptor was used to design these compounds. On that basis, the possibility to design novel potent inhibitors of Na⁺,K⁺-ATPase without being constrained by the stereochemistry of the classical digitalis skeleton in the D-ring region was predicted. The binding affinities of the most potent compounds in the two series, (EZ)-17α-{2-[(2-aminoethoxy)imino]ethyl}-5β-androstane-3β,14β-diol (6f) and (EZ)-3β-hydroxy-17α-{2-[(2-aminoethoxy)imino]ethyl}-14,15-seco-5β-androstan-14-one (24c) are higher than that of the potent natural compound digitoxigenin, despite the unusual α-exit of the substituent in position 17 of 6f or the disruption of the D-ring in 24c. These results further support the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve further investigation on the pharmacological profile of these derivatives.