title: Synthesis, cardiotonic activity, and structure-activity relationships of 17 beta-guanylhydrazone derivatives of 5 beta-androstane-3 beta, 14 beta-diol acting on the Na+,K(+)-ATPase receptor.
abstract: A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system.
authors.affiliation: Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese, MI, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cerri
authors.forename: F
authors.initials: F
authors.lastname: Serra
authors.forename: P
authors.initials: P
authors.lastname: Ferrari
authors.forename: E
authors.initials: E
authors.lastname: Folpini
authors.forename: G
authors.initials: G
authors.lastname: Padoani
authors.forename: P
authors.initials: P
authors.lastname: Melloni
mesh_terms: D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007668:Kidney / Q000201:enzymology; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000731:Androstanes; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; D000254:Sodium-Potassium-Exchanging ATPase