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) 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.
Abe
Y
Y
Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kayakiri
H
H
Satoh
S
S
Inoue
T
T
Sawada
Y
Y
Imai
K
K
Inamura
N
N
Asano
M
M
Hatori
C
C
Katayama
A
A
Oku
T
T
Tanaka
H
H
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
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