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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antidiuretic Hormone Receptor Antagonists*
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Arginine Vasopressin / antagonists & inhibitors*
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Azepines / chemical synthesis*
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Azepines / chemistry
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Azepines / pharmacology
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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Binding, Competitive
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Blood Platelets / drug effects
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Blood Platelets / metabolism
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CHO Cells
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Cricetinae
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Humans
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Hypertension / drug therapy
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In Vitro Techniques
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Kidney / drug effects
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Kidney / metabolism
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Liver / drug effects
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Liver / metabolism
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Male
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Membranes
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Models, Molecular
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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Antidiuretic Hormone Receptor Antagonists
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Azepines
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Benzamides
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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
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Thiophenes
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Arginine Vasopressin