title: Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine derivatives: novel arginine vasopressin antagonists.
abstract: 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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. hidetsura.cho@ims.jti.co.jp
authors.forename: Hidetsura
authors.initials: H
authors.lastname: Cho
authors.forename: Kengo
authors.initials: K
authors.lastname: Murakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Akitaka
authors.initials: A
authors.lastname: Fujisawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Isoshima
authors.forename: Misako
authors.initials: M
authors.lastname: Niwa
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hase
authors.forename: Itsuo
authors.initials: I
authors.lastname: Uchida
authors.forename: Hidenori
authors.initials: H
authors.lastname: Watanabe
authors.forename: Korekiyo
authors.initials: K
authors.lastname: Wakitani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Aisaka
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008566:Membranes; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D001549:Benzamides; C481782:N-(2-(4-(4-dimethylaminopiperidino)-4-oxobutoxy)-4-((5,6,7,8-tetrahydro-4H-thieno(3,2-b)azepin-4-yl)carbonyl)phenyl)-(1,1'-biphenyl)-2-carboxamide; D013876:Thiophenes; D001127:Arginine Vasopressin