title: Potent nonpeptide vasopressin receptor antagonists based on oxazino- and thiazinobenzodiazepine templates.
abstract: 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 V2 receptors. For example, (S)-(+)-8 and 5 are potent and selective V2 receptor antagonists with pronounced aquaretic activity in rats on oral administration.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. jmatthew@prdus.jnj.com
authors.forename: Jay M
authors.initials: JM
authors.lastname: Matthews
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: Alexey B
authors.initials: AB
authors.lastname: Dyatkin
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Hecker
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hlasta
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Poulter
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Eric
authors.initials: E
authors.lastname: Ericson
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Gunnet
authors.forename: William
authors.initials: W
authors.lastname: Hageman
authors.forename: Richard
authors.initials: R
authors.lastname: Look
authors.forename: John B
authors.initials: JB
authors.lastname: Moore
authors.forename: Charles H
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D004232:Diuretics / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010078:Oxazines / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D004232:Diuretics; D010078:Oxazines; D013843:Thiazines; D001569:Benzodiazepines