title: Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors.
abstract: Selective PDE3 (phosphodiesterase 3) inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this work ten new synthetic compounds (3-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]methylbenzamide analogs: 4a-j) were designed, synthesized and tested for the inhibitory activity against human PDE3A and PDE3B. The strategy of the design was based on the structure of vesnarinone (a selective PDE3 inhibitor) and its docking analysis results. The synthetic compounds showed better PDE3 inhibitory activity in comparison with vesnarinone. Using docking analysis, a common binding model of each compound toward PDE3 was suggested. In the next step the potential cardiotonic activity of the best PDE3A inhibitors (4b, IC(50)=0.43+/-0.04microM) was evaluated by using the spontaneously beating atria model. In the experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of the synthetic compound were assessed. That was carried out in comparison with vesnarinone. The best pharmacological profile was obtained for the compound 4b, which displayed selectivity for increasing the force of contraction (46+/-3% change over the control) rather than the frequency rate (16+/-4% change over the control) at 100microM.
authors.affiliation: Department of Chemistry, School of Sciences, Islamic Azad University, Ahvaz Branch, Ahvaz, 61349-68875, Islamic Republic of Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Nikpour
authors.forename: Hamid
authors.initials: H
authors.lastname: Sadeghian
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Saberi
authors.forename: Reza Shafiee
authors.initials: RS
authors.lastname: Nick
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Seyedi
authors.forename: Azar
authors.initials: A
authors.lastname: Hosseini
authors.forename: Heydar
authors.initials: H
authors.lastname: Parsaee
authors.forename: Alireza Taghian Dasht
authors.initials: AT
authors.lastname: Bozorg
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015195:Drug Design; D006801:Humans; D008297:Male; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C548631:3-((4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy)methylbenzamide; D001549:Benzamides; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human; C517291:PDE3B protein, human