| Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase: synthesis and structure-activity relationship. | |
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MedLine Citation:
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PMID: 18637667 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane. |
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Authors:
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Mauro Gobbini; Silvia Armaroli; Leonardo Banfi; Alessandra Benicchio; Giulio Carzana; Giorgio Fedrizzi; Patrizia Ferrari; Giuseppe Giacalone; Michele Giubileo; Giuseppe Marazzi; Rosella Micheletti; Barbara Moro; Marco Pozzi; Piero Enrico Scotti; Marco Torri; Alberto Cerri |
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Publication Detail:
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Type: Journal Article Date: 2008-07-19 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 51 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-07 Completed Date: 2008-09-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4601-8 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau SpA, Via Forlanini 3, Settimo Milanese, MI, Italy. mauro.gobbini@prassis.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amines
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chemistry Animals Etiocholanolone / analogs & derivatives*, chemical synthesis, chemistry, pharmacology Guinea Pigs Hydroxylation Models, Molecular Molecular Structure Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*, metabolism Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/3-((2-aminoethoxy)imino)androstane-6,17-dione; 0/Amines; 53-42-9/Etiocholanolone; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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