Potent nonpeptide vasopressin receptor antagonists based on oxazino- and thiazinobenzodiazepine templates.
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.
Matthews
Jay M
JM
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. jmatthew@prdus.jnj.com
Hoekstra
William J
WJ
Dyatkin
Alexey B
AB
Hecker
Leonard R
LR
Hlasta
Dennis J
DJ
Poulter
Brenda L
BL
Andrade-Gordon
Patricia
P
de Garavilla
Lawrence
L
Demarest
Keith T
KT
Ericson
Eric
E
Gunnet
Joseph W
JW
Hageman
William
W
Look
Richard
R
Moore
John B
JB
Reynolds
Charles H
CH
Maryanoff
Bruce E
BE
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
D065092:Antidiuretic Hormone Receptor Antagonists; D004232:Diuretics; D010078:Oxazines; D013843:Thiazines; D001569:Benzodiazepines