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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.
AuthorsHamid Sadeghian, Seyed Mohammad Seyedi, Mohammad Reza Saberi, Reza Shafiee Nick, Azar Hosseini, Mehdi Bakavoli, Seyed Mohammad Taghi Mansouri, Heydar Parsaee
JournalJournal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 24 Issue 4 Pg. 918-29 (Aug 2009) ISSN: 1475-6374 [Electronic] England
PMID19555170 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 6-hydroxymethylquinoline
  • Cardiotonic Agents
  • Phosphodiesterase Inhibitors
  • Quinolines
  • Quinolones
  • cilostamide
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Pde3a protein, rat
  • Pde3b protein, rat
  • Amrinone
  • 1-Methyl-3-isobutylxanthine
Topics
  • 1-Methyl-3-isobutylxanthine (pharmacology)
  • Amino Acid Sequence
  • Amrinone (pharmacology)
  • Animals
  • Atrial Function (drug effects)
  • Cardiotonic Agents (chemical synthesis, chemistry, pharmacology)
  • Catalytic Domain
  • Cyclic Nucleotide Phosphodiesterases, Type 3 (chemistry, genetics)
  • Drug Design
  • Molecular Sequence Data
  • Molecular Structure
  • Phosphodiesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Quinolines (chemical synthesis, chemistry, pharmacology)
  • Quinolones (pharmacology)
  • Rats
  • Rats, Wistar
  • Sequence Alignment

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