Glaß, D. and Buschauer, Armin and Tenor, H. and Bartel, S. and Will-Shahab, L. and Krause, E.-G. (1995) 4-(4-Guanidinobenzoyl)-2-imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H2 Receptor Agonist and PDE III Inhibitor Activity. ARCHIV DER PHARMAZIE, 328 (10). pp. 709-719. ISSN 0365-6233, 1521-4184
Full text not available from this repository.Abstract
A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H-2 receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H-2 agonism was incorporated by p-(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides 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 acid 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 H-2 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 H-2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H-2 antagonist famotidine (10 mu M) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H-2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H-2 agonist N-1-{4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)carbonyl]phenyl}-N-2-[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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; FAILING HUMAN MYOCARDIUM; HEART-FAILURE; PIMOBENDAN; CALCIUM; AGENTS; REPLACEMENT; ARPROMIDINE; MORTALITY; MECHANISM; CARDIOTONICS; PDE III INHIBITORS; HISTAMINE H-2 RECEPTOR AGONISTS; GUANIDINES; IMIDAZOLONES |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Jan 2024 08:55 |
| Last Modified: | 04 Jan 2024 08:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/52277 |
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