Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents.
Selective PDE3 inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this research we designed, synthesized and evaluated the potential cardiotonic activity of thirteen PDE3 inhibitors (4-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]butanamide analogs) using the spontaneously beating atria model. The design strategy was based on the structure of cilostamide, a selective PDE3 inhibitor. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthetic compounds were assessed. All experiments were carried out in comparison with IBMX, amrinone and cilostamide as standard compounds. The results showed that, among the new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, 4j, which displayed selectivity for increasing the force of contraction (165 +/- 4% change over the control) rather than the frequency rate (115 +/- 7% change over the control) at 100 microM and potent inhibitory activity of PDE3 with IC(50) = 0.20 microM.
Sadeghian
Hamid
H
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, IR Iran.
Seyedi
Seyed Mohammad
SM
Saberi
Mohammad Reza
MR
Nick
Reza Shafiee
RS
Hosseini
Azar
A
Bakavoli
Mehdi
M
Mansouri
Seyed Mohammad Taghi
SM
Parsaee
Heydar
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016415:Sequence Alignment
C115830:6-hydroxymethylquinoline; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015363:Quinolones; C021294:cilostamide; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517290:Pde3a protein, rat; C517294:Pde3b protein, rat; D000676:Amrinone; D015056:1-Methyl-3-isobutylxanthine