A new series of highly potent non-peptide bradykinin B2 receptor antagonists incorporating the 4-heteroarylquinoline framework. Improvement of aqueous solubility and new insights into species difference.
Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B(2) receptor antagonists resulted in enhancing binding affinities for the human B(2) receptor and reducing binding affinities for the guinea pig one, providing new structural insights into species difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B(2) receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [(3)H]BK to the cloned human B(2) receptor expressed in Chinese hamster ovary cells with an IC(50) value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 microg/kg by intravenous administration.
Sawada
Yuki
Y
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., 5-2-3 Tokodai, Tsukuba, Ibaraki 300-2698, Japan.
Kayakiri
Hiroshi
H
Abe
Yoshito
Y
Imai
Keisuke
K
Mizutani
Tsuyoshi
T
Inamura
Noriaki
N
Asano
Masayuki
M
Aramori
Ichiro
I
Hatori
Chie
C
Katayama
Akira
A
Oku
Teruo
T
Tanaka
Hirokazu
H
D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011917:Rats, Inbred Lew; D012995:Solubility; D013045:Species Specificity; D014867:Water
D065094:Bradykinin B2 Receptor Antagonists; D007093:Imidazoles; D011804:Quinolines; D014867:Water