A novel class of orally active non-peptide bradykinin B2 receptor antagonists.: 1.: Construction of the basic framework

A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B-2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-alpha]pyridine derivative 2. The unique screening lead (2) was discovered by a two-step intentional random screening process, involving recognition of the relationship between BK and angiotensin II (Ang II) and the common structural features. Systematic chemical modification of 2 elucidated the structural requirements essential for Bz binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-alpha]pyridine skeleton as the basic framework of this new series of Bz antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2,6-dichlorobenzene ring to allow these compounds to adopt the characteristic active conformation. The representative lead compounds inhibited the specific binding of [H-3]BK to guinea pig ileum membrane preparations expressing Bz receptors, with nanomolar IC(50)s and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea, pigs at an oral dose of 1 mg/kg. Pharmacokinetic studies of compounds 47c and 50b in rats highlighted their excellent oral bioavailabilities, indicating that they represent the first orally active nan-peptide Bz antagonists reported to date.