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A New Approach to the Design of Novel Inhibitors of Na+,K+-ATPase: 17α-Substituted Seco-D 5β-Androstane as Cassaine Analogues
Ist Teil von
Journal of medicinal chemistry, 1998-07, Vol.41 (16), p.3033-3040
Ort / Verlag
Washington, DC: American Chemical Society
Erscheinungsjahr
1998
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 17α-substituted derivatives of the digitalis 5β,14β-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 3β,14-dihydroxy-5β,14β-androstane-17α-acrylate 6 (IC50 = 5.89 μM) and, much more significantly, by the corresponding 14,15-seco-14-oxo derivative 9 (IC50 = 0.12 μM) substantiates the new hypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.