Document Report Card

ID: ALA1123810

Journal: J Med Chem

Title: Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones.

Authors: Bandurco VT, Schwender CF, Bell SC, Combs DW, Kanojia RM, Levine SD, Mulvey DM, Appollina MA, Reed MS, Malloy EA.

Abstract: 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.

CiteXplore: 3039135

DOI: 10.1021/jm00391a026