A Novel Class of Orally Active Non-Peptide Bradykinin B<sub>2</sub> Receptor Antagonists. 4. Discovery of Novel Frameworks Mimicking the Active Conformation

In recent articles we reported the identification of a series of 8-[[2,6-dichloro-3-[<i>N</i>-methyl-<i>N</i>-[(<i>E</i>)-(substituted)acryloylglycyl]amino]benzyl]oxy]-2-methylimidazo[1,2-<i>a</i>]pyridines as the first orally active non-peptide bradykinin (BK) B<sub>2</sub> receptor antagonists. Optimization of the terminal glycine part and the imidazo[1,2-<i>a</i>]pyridine moiety led to the discovery of a clinical candidate (<b>5</b>, 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 B<sub>2</sub> 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 <i>N</i>-methylamide group with <i>cis</i>-amide-like rigid moieties. We discovered several bioisosteres and chemically proved that the <i>N</i>-methylamide moiety adopts the <i>cis</i>-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 B<sub>2</sub> antagonists represented by a pyrrole derivative (<b>52a</b>, FR193517). Compound <b>52a</b> inhibited the specific binding of [<sup>3</sup>H]BK to recombinant human B<sub>2</sub> receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B<sub>2</sub> receptors with IC<sub>50</sub>s 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.