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

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)101-109
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number1
DOIs
Publication statusPublished - 2004 Jan 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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