17beta-O-Aminoalkyloximes of 5beta-androstane-3beta,14beta-diol with digitalis-like activity: synthesis, cardiotonic activity, structure-activity relationships, and molecular modeling of the Na(+),K(+)-ATPase receptor.
A series of digitalis-like compounds with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the receptor, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na(+),K(+)-ATPase inhibitory potencies (IC(50)) 17-25 times higher than the standards digitoxigenin and digoxin and 3-11 times higher inotropic potencies (EC(50)) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 domains of Na(+),K(+)-ATPase. Some interactions are the classical ones already described in the literature; a new, very strong interaction of the basic group with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compounds were also studied in vivo in the anesthetized guinea pig for evaluating their inotropic effect versus the lethal dose. Compounds 9 and 12 showed a slightly higher safety ratio than digoxin and deserve further evaluation.
Cerri
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Departments of Medicinal Chemistry and Cardiovascular Pharmacology, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese (MI), Italy. pstchem@tin.it
Almirante
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N
Barassi
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P
Benicchio
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A
Fedrizzi
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G
Ferrari
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P
Micheletti
R
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Quadri
L
L
Ragg
E
E
Rossi
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Santagostino
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M
Schiavone
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Serra
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Zappavigna
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Melloni
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D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004071:Digitalis Glycosides / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D008297:Male; D008958:Models, Molecular; D009200:Myocardial Contraction / Q000187:drug effects; D010042:Ouabain / Q000737:chemistry / Q000378:metabolism; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
C410931:17-(((4-aminobutoxy)imino)methyl)-5-androstane-3,14-diol; C410932:17-(3-((2-dimethylaminoethoxy)imino)propyl)-5-androstane-3,14-diol; D000731:Androstanes; D000732:Androstanols; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D004791:Enzyme Inhibitors; D010091:Oximes; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase