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Title: A new approach to the design of novel inhibitors of Na+,K+-ATPase: 17alpha-substituted seco-D 5beta-androstane as cassaine analogues. Author: De Munari S, Barassi P, Cerri A, Fedrizzi G, Gobbini M, Mabilia M, Melloni P. Journal: J Med Chem; 1998 Jul 30; 41(16):3033-40. PubMed ID: 9685243. 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.[Abstract] [Full Text] [Related] [New Search]