17 alpha-O-(aminoalkyl)oxime derivatives of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane as inhibitors of Na(+),K(+)-ATPase at the digitalis receptor.
The synthesis and binding affinities to the digitalis Na(+),K(+)-ATPase receptor of a series of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane derivatives bearing a 17 alpha-(aminoalkoxy)imino chain are reported; some derivatives were also studied for their inotropic activity. Our recently proposed model of interaction of molecules with the digitalis receptor was used to design these compounds. On that basis, the possibility to design novel potent inhibitors of Na(+),K(+)-ATPase without being constrained by the stereochemistry of the classical digitalis skeleton in the D-ring region was predicted. The binding affinities of the most potent compounds in the two series, (EZ)-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-5 beta-androstane-3 beta,14 beta-diol (6f) and (EZ)-3 beta-hydroxy-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-14,15-seco-5 beta-androstan-14-one (24c) are higher than that of the potent natural compound digitoxigenin, despite the unusual alpha-exit of the substituent in position 17 of 6f or the disruption of the D-ring in 24c. These results further support the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve further investigation on the pharmacological profile of these derivatives.
Gobbini
M
M
Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese (MI), Italy. pstchem@tin.it
Barassi
P
P
Cerri
A
A
De Munari
S
S
Fedrizzi
G
G
Santagostino
M
M
Schiavone
A
A
Torri
M
M
Melloni
P
P
D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D001667:Binding, Competitive; D004073:Digitoxigenin / Q000737:chemistry; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000737:chemistry; D008297:Male; D008958:Models, Molecular; D009200:Myocardial Contraction / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D012632:Secosteroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
C439949:17-(2-((2-aminoethoxy)imino)ethyl)androstane-3,14-diol; C439950:3-hydroxy-17-(2-((2-(N,N-dimethylamino)ethoxy)imino)ethyl)-14,15-secoandrostan-14-one; D000731:Androstanes; D000732:Androstanols; D004791:Enzyme Inhibitors; D010091:Oximes; D012632:Secosteroids; C027082:digitalis receptor; D004073:Digitoxigenin; D000254:Sodium-Potassium-Exchanging ATPase