Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase: synthesis and structure-activity relationship.
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.
Gobbini
Mauro
M
Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau SpA, Via Forlanini 3, Settimo Milanese, MI, Italy. mauro.gobbini@prassis.it
Armaroli
Silvia
S
Banfi
Leonardo
L
Benicchio
Alessandra
A
Carzana
Giulio
G
Fedrizzi
Giorgio
G
Ferrari
Patrizia
P
Giacalone
Giuseppe
G
Giubileo
Michele
M
Marazzi
Giuseppe
G
Micheletti
Rosella
R
Moro
Barbara
B
Pozzi
Marco
M
Scotti
Piero Enrico
PE
Torri
Marco
M
Cerri
Alberto
A
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
D000588:Amines; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; C468128:Istaroxime