In recent articles we reported the identification of a series of 8-[[2, 6-dichloro-3-[N-methyl-N-[(E)-(substituted)acryloylglycyl]amino]++ +benzy l]oxy]-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists. Optimization of the terminal glycine part and the imidazo[1,2-a]pyridine moiety led to the discovery of a clinical candidate (5, FR173657). With the aim of completion of the structure-activity relationship (SAR) study, we next investigated the roles of the substituents on the central phenyl ring. The results suggested that the 2,6-dichloro or 2, 6-dimethyl groups may play important roles in regulating the conformations of the 1- and 3-substituents and also may interact with hydrophobic pockets of the B2 receptors. Furthermore, according to the results of a molecular modeling study reported in part 1 of this series, we designed and synthesized a series of sterically constrained analogues by replacing the N-methylamide group with cis-amide-like rigid moieties. We discovered several bioisosteres and chemically proved that the N-methylamide moiety adopts the cis-amide form in the active conformation. Extensive chemical modification led to the identification of a novel class of highly potent and orally active non-peptide B2 antagonists represented by a pyrrole derivative (52a, FR193517). Compound 52a inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50s of 0.37 and 0.56 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration.