Cardiotonic agents. 5. Fragments from the heterocycle-phenyl-imidazole pharmacophore

• Published in: Journal of medicinal chemistry Vol. 32; no. 6; pp. 1173 - 1176
• Main Authors: Erhardt, Paul W, Hagedorn, Alfred A, Davey, David, Pease, Cynthia A, Venepalli, Bhaskar R, Griffin, Carl W, Gomez, Robert P, Wiggins, Jay R, Ingebretsen, William R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.06.1989
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animals; Benzoates - chemical synthesis; Benzoates - pharmacology; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - pharmacology; Dogs; Ferrets; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Molecular Structure; Myocardial Contraction - drug effects; Myocardium - enzymology; Stimulation, Chemical; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00126a005

To examine the role of each component in the heterocycle-phenyl-imidazole inotropic pharmacophore, several imidazolone derivatives, an arylimidazole, a substituted 3,4-dihydro-4-oxopyrimidine, and a quinolin-2(1H)-one derivative were prepared as structural fragments or representatives from this relationship. Tests for cardiac inotropic activity in ferret papillary muscle strips (FPM) and for inhibition of crude cAMP phosphodiesterase obtained from canine cardiac tissue suggest that, while all three components contribute significantly toward potent activity (active at less than 1 microM concentrations in FPM), any combination of two components, in approximately a preferred geometry, represents the minimal requirements for weak activity (active at less than 25 microM concentrations). No single component appears to be requisite in an absolute sense.