title: A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework.
abstract: A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-a]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 B2 binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo- 2- methylimidazo[1,2-a]pyridine skeleton as the basic framework of this new series of B2 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 [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors, with nanomolar IC50S 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 non-peptide B2 antagonists reported to date.
authors.affiliation: Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: H
authors.initials: H
authors.lastname: Kayakiri
authors.forename: S
authors.initials: S
authors.lastname: Satoh
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: K
authors.initials: K
authors.lastname: Imai
authors.forename: N
authors.initials: N
authors.lastname: Inamura
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: C
authors.initials: C
authors.lastname: Hatori
authors.forename: A
authors.initials: A
authors.lastname: Katayama
authors.forename: T
authors.initials: T
authors.lastname: Oku
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001920:Bradykinin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065168:Bradykinin Receptor Antagonists; D001993:Bronchodilator Agents; D007093:Imidazoles; D007202:Indicators and Reagents; D011725:Pyridines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D000804:Angiotensin II; D001920:Bradykinin