Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine derivatives:: Novel arginine vasopressin antagonists

被引：28

作者：

Cho, H ^{[1
]}

Murakami, K ^{[1
]}

Nakanishi, H ^{[1
]}

Fujisawa, AK ^{[1
]}

Isoshima, H ^{[1
]}

Niwa, M ^{[1
]}

Hayakawa, K ^{[1
]}

Hase, Y ^{[1
]}

Uchida, I ^{[1
]}

Watanabe, H ^{[1
]}

Wakitani, K ^{[1
]}

Aisaka, K ^{[1
]}

机构：

[1] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Takatsuki, Osaka 5691125, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 01期

关键词：

D O I：

10.1021/jm030287l

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [H-3]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure-activity relationships of these compounds, the thienoazepine derivative 1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride 2 (JTV-605) of compound 1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.

引用

页码：101 / 109

页数：9