4-(4-Guanidinobenzoyl)-2-imidazolones and related compounds: Phosphodiesterase inhibitors and novel cardiotonics with combined histamine H2 receptor agonist and PDE III inhibitor activity

Article abstract of DOI:10.1002/ardp.19953281005

A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazole-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H₂ receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H₂ agonism was incorporated by p-(hetero)alkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines carboxylate, and amines were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated from 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 H₂ receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H₂ receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H₂ antagonist famotidine (10 μM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H₂ receptor binding assay. At equieffective concentrations the moderate PDE III inhibitor and histamine H₂ agonist N¹-{4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)-carbonyl]phenyl }-N²-[3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-ethyl 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.