title: Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase: synthesis and structure-activity relationship.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau SpA, Via Forlanini 3, Settimo Milanese, MI, Italy. mauro.gobbini@prassis.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Gobbini
authors.forename: Silvia
authors.initials: S
authors.lastname: Armaroli
authors.forename: Leonardo
authors.initials: L
authors.lastname: Banfi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Benicchio
authors.forename: Giulio
authors.initials: G
authors.lastname: Carzana
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fedrizzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giacalone
authors.forename: Michele
authors.initials: M
authors.lastname: Giubileo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marazzi
authors.forename: Rosella
authors.initials: R
authors.lastname: Micheletti
authors.forename: Barbara
authors.initials: B
authors.lastname: Moro
authors.forename: Marco
authors.initials: M
authors.lastname: Pozzi
authors.forename: Piero Enrico
authors.initials: PE
authors.lastname: Scotti
authors.forename: Marco
authors.initials: M
authors.lastname: Torri
authors.forename: Alberto
authors.initials: A
authors.lastname: Cerri
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006900:Hydroxylation; D008958:Models, Molecular; D015394:Molecular Structure; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; C468128:Istaroxime