Simplified digitalis-like compounds acting on Na(+), K(+)-ATPase.
Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of Na(+),K(+)-ATPase. A well-known drawback is their arrhythmogenic potential. Attempts to find safer digitalis-like compounds by means of molecular simplifications of the typical 5beta,14beta-steroidal skeleton, which appeared in the medicinal chemistry literature from 1990 until 2002, are briefly reviewed. Several novel achievements were obtained in order to better understand the requisites of the digitalis binding site on Na(+), K(+)-ATPase. Only minor simplification, such as cleavage of the D ring of the digitalis skeleton, could preserve the desired inotropic activity, while highly simplified digitalis-like compounds failed to give sufficiently high inotropic potency, even in the presence of a powerful pharmacophore, such as the O-aminoalkyloxime group.
Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, MI, Italy. alberto.cerri@prassis.it
Alberto
A
Cerri
Mauro
M
Gobbini
D000818:Animals; D002298:Cardenolides; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004071:Digitalis Glycosides / Q000737:chemistry / Q000494:pharmacology; D004077:Digoxin / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D012503:Saponins / Q000737:chemistry* / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D002298:Cardenolides; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D004791:Enzyme Inhibitors; D012503:Saponins; C034504:digoxin-like factors; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase