A Novel Class of Orally Active Non-Peptide Bradykinin B<sub>2</sub> Receptor Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-<i>a</i>]pyridine Moiety

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B<sub>2</sub> receptor antagonists, incorporating an 8-[[3-(<i>N</i>-acylglycyl-<i>N</i>-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-<i>a</i>]pyridine skeleton, leading to identification of the first clinical candidate <b>4a</b> (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-<i>a</i>]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure−activity relationships (SAR) around the imidazo[1,2-<i>a</i>]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate <b>87b</b> (FR173657) which 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 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED<sub>50</sub> value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of <b>99</b> (FR184280), whose IC<sub>50</sub> value for human B<sub>2</sub> receptors (0.51 nM) was comparable to that of the second-generation peptide B<sub>2</sub> antagonist Icatibant.