Journal of Medicinal Chemistry 2004-01-01

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

Hidetsura Cho, Kengo Murakami, Hiroyuki Nakanishi, Akitaka Fujisawa, Hirotaka Isoshima, Misako Niwa, Kazuhide Hayakawa, Yasunori Hase, Itsuo Uchida, Hidenori Watanabe, Korekiyo Wakitani, Kazuo Aisaka

文献索引：J. Med. Chem. 47 , 101-109, (2004)

全文：HTML全文

摘要

A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [(3)H]-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.