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

We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na(+),K(+)-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na(+),K(+)-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency.