title: Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents.
abstract: 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.
authors: Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, IR Iran.
authors: Hamid
authors: H
authors: Sadeghian
authors: Seyed Mohammad
authors: SM
authors: Seyedi
authors: Mohammad Reza
authors: MR
authors: Saberi
authors: Reza Shafiee
authors: RS
authors: Nick
authors: Azar
authors: A
authors: Hosseini
authors: Mehdi
authors: M
authors: Bakavoli
authors: Seyed Mohammad Taghi
authors: SM
authors: Mansouri
authors: Heydar
authors: H
authors: Parsaee
mesh_terms: 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
chemical_list: 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