A Novel Class of Orally Active Non-Peptide Bradykinin B₂ Receptor Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-a]pyridine Moiety

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B₂ receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (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-a]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-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which 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 IC₅₀'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 ED₅₀ 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 99 (FR184280), whose IC₅₀ value for human B₂ receptors (0.51 nM) was comparable to that of the second-generation peptide B₂ antagonist Icatibant.