A New Approach to the Design of Novel Inhibitors of Na+,K+-ATPase: 17-Substituted Seco-D 5
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- 作者：Sergio De Munari ; Paolo Barassi ; Alberto Cerri ; Giorgio Fedrizzi ; Mauro Gobbini ; Massimo Mabilia ; and Piero Melloni
- 刊名：Journal of Medicinal Chemistry
- 出版年：1998
- 出版时间：July 30, 1998
- 年：1998
- 卷：41
- 期：16
- 页码：3033 - 3040
- 全文大小：209K
- 年卷期：v.41,no.16(July 30, 1998)
- ISSN：1520-4804
文摘
A new three-dimensional model for the relative binding mode of cassaine 1 and digitoxigenin2 at the digitalis receptor site is proposed on the basis of the structural and conformationalsimilarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculationthat also 17
-substituted derivatives of the digitalis 5
,14-androstane skeleton could efficientlybind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of somerelated compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3,14-dihydroxy-5,14-androstane-17-acrylate 6 (IC50 = 5.89 
M) and, much more significantly,by the corresponding 14,15-seco-14-oxo derivative 9 (IC50 = 0.12 M) substantiates the newhypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase aspotential positive inotropic compounds.
-substituted derivatives of the digitalis 5,14-androstane skeleton could efficientlybind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of somerelated compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3,14-dihydroxy-5,14-androstane-17-acrylate 6 (IC50 = 5.89 M) and, much more significantly,by the corresponding 14,15-seco-14-oxo derivative 9 (IC50 = 0.12 M) substantiates the newhypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase aspotential positive inotropic compounds.