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

doi:10.1021/jm030287l

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 journal › Article › peer-review

34 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 language	English
Pages (from-to)	101-109
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	1
DOIs	https://doi.org/10.1021/jm030287l
Publication status	Published - 2004 Jan 1
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Cho, H., Murakami, K., Nakanishi, H., Fujisawa, A., Isoshima, H., Niwa, M., Hayakawa, K., Hase, Y., Uchida, I., Watanabe, H., Wakitani, K., & Aisaka, K. (2004). Synthesis and Structure-Activity Relationships of 5,6,7,8-Tetrahydro-4H-thieno[3,2-b]azepine Derivatives: Novel Arginine Vasopressin Antagonists. Journal of Medicinal Chemistry, 47(1), 101-109. https://doi.org/10.1021/jm030287l

Cho, H, Murakami, K, Nakanishi, H, Fujisawa, A, Isoshima, H, Niwa, M, Hayakawa, K, Hase, Y, Uchida, I, Watanabe, H, Wakitani, K & Aisaka, K 2004, 'Synthesis and Structure-Activity Relationships of 5,6,7,8-Tetrahydro-4H-thieno[3,2-b]azepine Derivatives: Novel Arginine Vasopressin Antagonists', Journal of Medicinal Chemistry, vol. 47, no. 1, pp. 101-109. https://doi.org/10.1021/jm030287l

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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.",

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AU - Niwa, Misako

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AU - Hase, Yasunori

AU - Uchida, Itsuo

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Synthesis and Structure-Activity Relationships of 5,6,7,8-Tetrahydro-4H-thieno[3,2-b]azepine Derivatives: Novel Arginine Vasopressin Antagonists

Abstract

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