A New Approach to the Design of Novel Inhibitors of Na+,K+-ATPase: 17α-Substituted Seco-D 5β-Androstane as Cassaine Analogues
- 1 July 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (16) , 3033-3040
- https://doi.org/10.1021/jm980108d
Abstract
A new three-dimensional model for the relative binding mode of cassaine 1 and digitoxigenin 2 at the digitalis receptor site is proposed on the basis of the structural and conformational similarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculation that also 17alpha-substituted derivatives of the digitalis 5beta,14beta-androstane skeleton could efficiently bind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of some related compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3beta, 14-dihydroxy-5beta,14beta-androstane-17alpha-acrylate 6 (IC50 = 5.89 microM) and, much more significantly, by the corresponding 14, 15-seco-14-oxo derivative 9 (IC50 = 0.12 microM) substantiates the new hypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.Keywords
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