title: Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds.
abstract: The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses.
authors.affiliation: Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: De Munari
authors.forename: Alberto
authors.initials: A
authors.lastname: Cerri
authors.forename: Mauro
authors.initials: M
authors.lastname: Gobbini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Almirante
authors.forename: Leonardo
authors.initials: L
authors.lastname: Banfi
authors.forename: Giulio
authors.initials: G
authors.lastname: Carzana
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marazzi
authors.forename: Rosella
authors.initials: R
authors.lastname: Micheletti
authors.forename: Antonio
authors.initials: A
authors.lastname: Schiavone
authors.forename: Simona
authors.initials: S
authors.lastname: Sputore
authors.forename: Marco
authors.initials: M
authors.lastname: Torri
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Zappavigna
authors.forename: Piero
authors.initials: P
authors.lastname: Melloni
mesh_terms: D000731:Androstanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006168:Guinea Pigs; D008958:Models, Molecular; D009200:Myocardial Contraction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
chemical_list: D000731:Androstanes; D004791:Enzyme Inhibitors; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; C468128:Istaroxime