Discovery of Non peptide Bradykinin B2 Receptor Antagonists and Agonists

A novel class of potent and selective non-peptide bradykinin (BK) B2 receptor antagonists and agonists was designed and synthesized. The unique screening lead (9) was discovered by a two-step directed random screening process. Systematic chemical modification of 9 elucidated the structural requirements essential for the B2 binding affinity, leading to the identification of the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2, 6-dichlorophenyl ring to allow these compounds to adopt the characteristic active conformation. It was further revealed that the 4-substituent of the quinoline moiety is the key pharmacophore to determine the agonist/antagonist profiles. During these studies, we discovered the orally active non-peptide B2 antagonist, FK 3657 (2), which is undergoing clinical development, and potent B2 agonists represented by FR 190997 (5) and FR 198100 (6).