FROM PEPTIDE TO NONPEPTIDE .3. ATROPISOMERIC GPIIBIIIA ANTAGONISTS CONTAINING THE 3,4-DIHYDRO-1H-1,4-BENZODIAZEPINE-2,5-DIONE NUCLEUS

The benzodiazepinedione class of non-peptidal GPIIbIIIa antagonists ha s been modified to allow the isolation of noninterconverting rotationa l isomers, or atropisomers, with the aim of examining their structure- activity relationships as compared to active RGD-containing peptides a nd other non-peptidal antagonists. Resolution of these antagonists was accomplished by the introduction of a tert-butyl group at N1 and a ch lorine at C9 on the 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione nucleu s and enantiospecific substitution on the beta-alanine side chain atta ched to N4. The relative configuration was determined by single-crysta l X-ray analysis. Further, conformational analyses using ab initio cal culations were performed to assess the conformational preferences abou t the beta-alanine side chain. The data support a good topographical c orrelation between the benzodiazepinedione class of antagonists and th e ''cupped'' presentation of the RGD tripeptide sequence found in the cyclic peptide G4120. The relationship between these compounds with ot her peptidal and non-peptidal antagonists is discussed.