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

被引:57
作者
Sawada, Y [1 ]
Kayakiri, H [1 ]
Abe, Y [1 ]
Imai, K [1 ]
Mizutani, T [1 ]
Inamura, N [1 ]
Asano, M [1 ]
Aramori, I [1 ]
Hatori, C [1 ]
Katayama, A [1 ]
Oku, T [1 ]
Tanaka, H [1 ]
机构
[1] Fujisawa Pharmaceut Co Ltd, Exploratory Res Labs, Tsukuba, Ibaraki 3002698, Japan
关键词
D O I
10.1021/jm030159x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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-(I-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 [H-3]BK to the cloned human B-2 receptor expressed in Chinese hamster ovary cells with an IC50 value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 mug/kg by intravenous administration.
引用
收藏
页码:1617 / 1630
页数:14
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