Abstract
Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of the Na+,K+-ATPase. A well-known drawback is their arrhythmogenic potential together with a low therapeutic index. Digitalis compounds are characterized by a cis/trans/cis steroidal skeleton with an α, β-unsaturated lactone ( γ-butyrolactone) in the 17 β-position, a 14 β- hydroxy group and a 3 β-hydroxy group, the latter usually linked to one or more sugar rings. The first three moieties are considered essential for inotropic activity, while the glycosides are responsible for the pharmacokinetics of the compounds. This review briefly reports on some of the replacements for the unsaturated γ-butyrolactone moiety and then summarizes the work at Prassis that led to the discovery of the O-aminoalkyloxime group as a very powerful substitute. We also report on the development of new steroidal compounds which act as digitalis-like inhibitors of the Na+,K+-ATPase, without any of the chemical features that are peculiar to naturally occurring digitalis glycosides.
Keywords: digitalis-like compounds, k atpase, unsaturated -butyrolactone, o-aminoalkyloxime, congestive heart failure, inotropic
Current Medicinal Chemistry
Title: Digitalis-like Compounds: the Discovery of the O-aminoalkyloxime Group as a Very Powerful Substitute for the Unsaturated γ-Butyrolactone Moiety
Volume: 12 Issue: 20
Author(s): Mauro Gobbini and Alberto Cerri
Affiliation:
Keywords: digitalis-like compounds, k atpase, unsaturated -butyrolactone, o-aminoalkyloxime, congestive heart failure, inotropic
Abstract: Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of the Na+,K+-ATPase. A well-known drawback is their arrhythmogenic potential together with a low therapeutic index. Digitalis compounds are characterized by a cis/trans/cis steroidal skeleton with an α, β-unsaturated lactone ( γ-butyrolactone) in the 17 β-position, a 14 β- hydroxy group and a 3 β-hydroxy group, the latter usually linked to one or more sugar rings. The first three moieties are considered essential for inotropic activity, while the glycosides are responsible for the pharmacokinetics of the compounds. This review briefly reports on some of the replacements for the unsaturated γ-butyrolactone moiety and then summarizes the work at Prassis that led to the discovery of the O-aminoalkyloxime group as a very powerful substitute. We also report on the development of new steroidal compounds which act as digitalis-like inhibitors of the Na+,K+-ATPase, without any of the chemical features that are peculiar to naturally occurring digitalis glycosides.
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Cite this article as:
Gobbini Mauro and Cerri Alberto, Digitalis-like Compounds: the Discovery of the O-aminoalkyloxime Group as a Very Powerful Substitute for the Unsaturated γ-Butyrolactone Moiety, Current Medicinal Chemistry 2005; 12 (20) . https://dx.doi.org/10.2174/0929867054864787
DOI https://dx.doi.org/10.2174/0929867054864787 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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