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Synthesis and Inotropic Activity of 1-(O-Aminoalkyloximes) of Perhydroindene Derivatives as Simplified Digitalis-like Compounds Acting on the Na+,K+-ATPase
- Source :
- Journal of Medicinal Chemistry. 45:189-207
- Publication Year :
- 2001
- Publisher :
- American Chemical Society (ACS), 2001.
-
Abstract
- A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-ol derivatives bearing a 1(S)-(omega-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-Parrish ketol 47, as simplified analogues of very potent 17beta-aminoalkyloximes with digitalis skeleton, previously reported. The target compounds were evaluated in vitro for displacement of the specific [3H]ouabain binding from the dog kidney Na(+),K(+)-ATPase receptor. Some of them revealed IC(50) values in the micromolar range. The most active compounds possess a cyclohexyl group in the 5(S) position and in position 1(S) the same aminoalkyloxime groups already reported for the digitoxigenin-like series in position 17beta. Although the ring conformation of these derivatives was comparable to that of uzarigenin, the binding affinities of the most active ones were 4/8-fold lower in comparison to that standard. Three compounds among those with the highest affinities were assayed in vitro for their inotropic activity on an electrically driven guinea pig left atrium and were found to be less potent than both digoxin, the most widely used inotropic agent, and the corresponding digitalis 17beta-aminoalkyloximes.
- Subjects :
- Digoxin
Cardiotonic Agents
Tertiary amine
Stereochemistry
Guinea Pigs
Substituent
Digitalis
In Vitro Techniques
Kidney
Binding, Competitive
Chemical synthesis
Radioligand Assay
Structure-Activity Relationship
chemistry.chemical_compound
Dogs
Oximes
Drug Discovery
Animals
Heart Atria
Na+/K+-ATPase
chemistry.chemical_classification
Bicyclic molecule
biology
Ligand
Digitalis Glycosides
Stereoisomerism
Atrial Function
biology.organism_classification
Myocardial Contraction
Enzyme
Indenes
chemistry
Molecular Medicine
Sodium-Potassium-Exchanging ATPase
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....cbb7f4b886d7317e8a6e45c67d2d7670