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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 07期

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

页码：1617 / 1630

页数：14

共 49 条

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