17α-O-(Aminoalkyl)oxime Derivatives of 3β,14β-Dihydroxy-5β-androstane and 3β-Hydroxy-14-oxoseco-D-5β-androstane as Inhibitors of Na+,K+-ATPase at the Digitalis Receptor
| Autor: | Paolo Barassi, Marco Santagostino, Mauro Gobbini, Giorgio Fedrizzi, Marco Torri, Antonio Schiavone, Piero Melloni, Alberto Cerri, De Munari S |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
Models Molecular Stereochemistry Guinea Pigs Substituent Digitalis In Vitro Techniques Kidney Binding Competitive Guinea pig Radioligand Assay chemistry.chemical_compound Dogs Oximes Drug Discovery Animals Secosteroids Androstanols Heart Atria Enzyme Inhibitors Na+/K+-ATPase Receptor Digitoxigenin biology Chemistry Atrial Function Oxime biology.organism_classification Myocardial Contraction Molecular Medicine Androstane Sodium-Potassium-Exchanging ATPase Androstanes |
| Zdroj: | Journal of Medicinal Chemistry. 44:3821-3830 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The synthesis and binding affinities to the digitalis Na(+),K(+)-ATPase receptor of a series of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane derivatives bearing a 17 alpha-(aminoalkoxy)imino chain are reported; some derivatives were also studied for their inotropic activity. Our recently proposed model of interaction of molecules with the digitalis receptor was used to design these compounds. On that basis, the possibility to design novel potent inhibitors of Na(+),K(+)-ATPase without being constrained by the stereochemistry of the classical digitalis skeleton in the D-ring region was predicted. The binding affinities of the most potent compounds in the two series, (EZ)-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-5 beta-androstane-3 beta,14 beta-diol (6f) and (EZ)-3 beta-hydroxy-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-14,15-seco-5 beta-androstan-14-one (24c) are higher than that of the potent natural compound digitoxigenin, despite the unusual alpha-exit of the substituent in position 17 of 6f or the disruption of the D-ring in 24c. These results further support the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve further investigation on the pharmacological profile of these derivatives. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|