Discovery of dihydroquinoxalinone acetamides containing bicyclic amines as potent Bradykinin B1 receptor antagonists.
Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-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(50)s<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.
Chen
Jian Jeffrey
JJ
Chemistry Research and Development, Amgen Inc., One Amgen Center Drive, MS-B29-4-1-B, Thousand Oaks, CA 91320, USA. jianc@amgen.com
Qian
Wenyuan
W
Biswas
Kaustav
K
Viswanadhan
Vellarkad N
VN
Askew
Benny C
BC
Hitchcock
Stephen
S
Hungate
Randall W
RW
Arik
Leyla
L
Johnson
Eileen
E
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry; D019342:Acetic Acid / Q000737:chemistry; D000588:Amines; D065169:Bradykinin B1 Receptor Antagonists; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D043783:Receptor, Bradykinin B1 / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000588:Amines; D065169:Bradykinin B1 Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines; D043783:Receptor, Bradykinin B1; D019342:Acetic Acid