Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones
| Autor: | Charles F. Schwender, E. A. Malloy, Ramesh M. Kanojia, Stanley C Bell, Dennis M. Mulvey, Donald W. Combs, Seymour D. Levine, Bandurco Victor T, M. S. Reed, M. A. Appollina |
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| Rok vydání: | 1987 |
| Předmět: |
Chemical Phenomena
medicine.drug_class Stereochemistry Carboxamide Blood Pressure Amrinone chemistry.chemical_compound Structure-Activity Relationship Dogs Heart Rate Drug Discovery medicine Quinazoline Animals biology Cyclic nucleotide phosphodiesterase Bicyclic molecule Myocardium Biological activity Myocardial Contraction Stimulation Chemical Chemistry chemistry Enzyme inhibitor 3' 5'-Cyclic-AMP Phosphodiesterases biology.protein Quinazolines Molecular Medicine Potassium cyanate medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 30(8) |
| ISSN: | 0022-2623 |
| Popis: | The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic. |
| Databáze: | OpenAIRE |
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