4-(4-GUANIDINOBENZOYL)-2-IMIDAZOLONES AND RELATED-COMPOUNDS - PHOSPHODIESTERASE INHIBITORS AND NOVEL CARDIOTONICS WITH COMBINED HISTAMINE H-2-RECEPTOR AGONIST AND PDE-III INHIBITOR ACTIVITY

A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodieste rase (PDE) inhibitor enoximone and guanidine-type histamine H-2 recept or agonists such as arpromidine. All compounds are para-substituted 4- benzoyl-5-alkyl-2-imidazolones. H-2 agonism was incorporated by p-(het ero)arylalkyl substituents, in particular by an imidazolylpropyl guani dine group. In addition analogous ureas, cyanoguanidines, alkyl guanid ine carboxylates, and amides were prepared. These functional groups we re either directly attached to the phenyl ring or linked by an appropr iate spacer. The compounds were screened for positive inotropic activi ty in the isolated electrically stimulated guinea pig papillary muscle acid for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated fro m guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3-fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H-2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, pr obably due to their synergistic mechanism of action, The participation of histamine H-2 receptors could be demonstrated in the papillary mus cle preparation by pretreatment with the H-2 antagonist famotidine (10 mu M) as well as by further pharmacological experiments using isolate d perfused hearts of guinea pigs and rats, isolated guinea pig right a tria, adenylyl cyclase and H-2 receptor binding assays. At equieffecti ve concentrations the moderate PDE III inhibitor and histamine H-2 ago nist ]phenyl}-N-2-[3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-e thyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5-fold higher maximal response than the reference compound.