Potent nonpeptide vasopressin receptor antagonists based on oxazino- and thiazinobenzodiazepine templates

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 11; pp. 2747 - 2752
• Main Authors: Matthews, Jay M., Hoekstra, William J., Dyatkin, Alexey B., Hecker, Leonard R., Hlasta, Dennis J., Poulter, Brenda L., Andrade-Gordon, Patricia, de Garavilla, Lawrence, Demarest, Keith T., Ericson, Eric, Gunnet, Joseph W., Hageman, William, Look, Richard, Moore, John B., Reynolds, Charles H., Maryanoff, Bruce E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 07.06.2004; Elsevier
• Subjects: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Benzodiazepines - chemical synthesis; Benzodiazepines - pharmacology; Biological and medical sciences; Diuretics - chemical synthesis; Diuretics - pharmacology; Dose-Response Relationship, Drug; Humans; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oxazines - chemistry; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Protein Binding; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazines - chemistry; Enantiomer(+); Rat; 8-Arginine vasopressin; Non peptide compound; Selectivity; Diuretic; Structure activity relation; V2 vasopressin receptor; Aromatic compound; Antagonist; Chemical synthesis; Vasopressin receptor; Oxygen nitrogen heterocycle; Sulfur nitrogen heterocycle; Rodentia; Oral administration; Tricyclic compound; Organic chlorine compounds; In vitro; In vivo; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Carboxamide; S configuration
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.03.083

Graphic Vasopressin receptor antagonists can elicit ion-sparing diuretic effects (i.e., aquaresis) in vivo by blunting the action of the circulating hypophyseal hormone arginine vasopressin. We have identified two new series of basic tricyclic benzodiazepines, represented by general structure 1, which contain compounds that bind with high affinity to human V 2 receptors. For example, ( S)-(+)- 8 and 5 are potent and selective V 2 receptor antagonists with pronounced aquaretic activity in rats on oral administration.