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Digitalis-like Compounds: the Discovery of the O-aminoalkyloxime Group as a Very Powerful Substitute for the Unsaturated γ-Butyrolactone Moiety

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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: congestive heart failure; digitalis-like compounds; inotropic; k atpase; o-aminoalkyloxime; unsaturated -butyrolactone

Document Type: Review Article


Affiliations: Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini, 3, 20019 Settimo Milanese (MI), Italy.

Publication date: September 1, 2005

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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