Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists

Novel dihydroquinoxalinone acetamides containing bicyclic aminotetralins or chromans were found to be potent Bradykinin B1 receptor antagonists. Replacement of the core β-amino acid in our previously reported piperidine acetic acid and β-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC 50s < 0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure–activity relationship (SAR) for these analogs.