From Peptide to Non-Peptide. 3. Atropisomeric GPIIbIIIa Antagonists Containing the 3,4-Dihydro-1<i>H</i>-1,4-benzodiazepine-2,5-dione Nucleus

Abstract

The benzodiazepinedione class of non-peptidal GPIIbIIIa antagonists has been modified to allow the isolation of noninterconverting rotational isomers, or atropisomers, with the aim of examining their structure-activity relationships as compared to active RGD-containing peptides and other non-peptidal antagonists. Resolution of these antagonists was accomplished by the introduction of a tert-butyl group at N1 and a chlorine at C9 on the 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione nucleus and enantiospecific substitution on the beta-alanine side chain attached to N4. The relative configuration was determined by single-crystal X-ray analysis. Further, conformational analyses using ab initio calculations were performed to assess the conformational preferences about the beta-alanine side chain. The data support a good topographical correlation between the benzodiazepinedione class of antagonists and the "cupped" presentation of the RGD tripeptide sequence found in the cyclic peptide G4120. The relationship between these compounds with other peptidal and non-peptidal antagonists is discussed.