Synthesis, Cardiotonic Activity, and Structure−Activity Relationships of 17β-Guanylhydrazone Derivatives of 5β-Androstane-3β,14β-diol Acting on the Na+,K+-ATPase Receptor
| Autor: | Elena Folpini, Piero Melloni, Patrizia Ferrari, Gloria Padoani, Fulvio Serra, Alberto Cerri |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Cardiotonic Agents
Stereochemistry Digitoxin Guinea Pigs Kidney Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery medicine Animals Structure–activity relationship Enzyme Inhibitors Na+/K+-ATPase Beta (finance) Molecular Structure biology Hydrazones Arrhythmias Cardiac Myocardial Contraction Digitoxigenin chemistry Enzyme inhibitor biology.protein Molecular Medicine Androstane Sodium-Potassium-Exchanging ATPase Androstanes medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 40:3484-3488 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970312l |
| Popis: | A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system. |
| Databáze: | OpenAIRE |
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