Synthesis and inotropic activity of 1-(O-aminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na(+),K(+)-ATPase.
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.
Cerri
Alberto
A
Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese (MI), Italy. pstchem@tin.it
Almirante
Nicoletta
N
Barassi
Paolo
P
Benicchio
Alessandra
A
De Munari
Sergio
S
Marazzi
Giuseppe
G
Molinari
Isabella
I
Serra
Fulvio
F
Melloni
Piero
P
D000818:Animals; D016275:Atrial Function; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004071:Digitalis Glycosides / Q000737:chemistry* / Q000494:pharmacology; D004077:Digoxin / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D007192:Indenes; D010091:Oximes; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase